Examining Traumatic Brain Injury as a Chronic Condition: Proceedings of a Workshop (2025)

Below is the uncorrected machine-read text of this chapter, intended to provide our own search engines and external engines with highly rich, chapter-representative searchable text of each book. Because it is UNCORRECTED material, please consider the following text as a useful but insufficient proxy for the authoritative book pages.

2 Exploring the Evidence for Characterizing Traumatic Brain Injury as a Chronic Condition Key Points Highlighted by Individual Speakers • TBI can lead to long-term sequelae across physical, cognitive, emo- tional, and social domains, with outcomes that evolve over time rather than remaining static. These impacts may persist years after the initial injury and can significantly affect independence, employment, and social participation (Dams-O’Connor, Sander). • TBI is linked to higher risks of mortality, disability, cognitive decline, dementia, epilepsy, stroke, falls, frailty, and psychiatric and medical comorbidities. The number and severity of TBIs compound these risks, underscoring the need for long-term monitoring and care (Sander, Schneider). • A paradigm shift is needed that moves away from viewing TBI as an acute event. This includes improving TBI screening, adopting longi- tudinal care models, broadening inclusion in research and services, and using epidemiologic and other data to address knowledge gaps (Corrigan, Sander). • Outcomes after TBI are shaped by multiple, interconnected factors, including comorbidities, age, socioeconomic status, injury history, and access to care, requiring a multifaceted and person-centered approach to treatment and support (Sander). • Research is needed to better understand such areas as comorbidity interactions, cognitive changes over time, sex differences in TBI injury and recovery, and developmental timing of injury (Corrigan, Sander, Schneider). continued 9 PREPUBLICATION COPY—Uncorrected Proofs 

10 EXAMINING TBI AS A CHRONIC CONDITION • TBI triggers long-term neuroinflammation and can hasten age-related neuropathology and cognitive impairment, with molecular evidence of neuroinflammation detected even decades postinjury (Loane). • Moderate to severe TBI can initiate systemic inflammation that evolves from acute immunosuppression to chronic immune dysfunc- tion, increasing susceptibility to infections and comorbidities. This underscores the need to treat TBI as a systemic condition, not solely a neurological one (Loane). • Drugs targeting specific inflammatory pathways could help prevent or slow neurodegeneration after TBI. These findings expand the potential therapeutic window beyond the acute phase of injury (Loane). • Biomarker-based approaches, such as the Rehabilomics model, which maps inflammatory biomarkers to functional outcomes, reveal how inflammatory load influences cognition, independence, and quality of life. This approach supports development of tailored and individual- ized treatments (Wagner). • Developments in scalable biomarker technologies integrated with point-of-care diagnostics and telehealth may enable greater real-time monitoring and personalized treatment in community settings, to sup- port long-term recovery. (Wagner) • Individuals with TBI are eight times more likely to develop major depression in the first year postinjury, with potentially long-lasting effects, even among those with no prior history of mental health issues. Depression is closely linked to other conditions including pain, cognitive dysfunction, and insomnia, and treating these can improve depressive symptoms (Bombardier). • Post-traumatic epilepsy can pose a significant psychosocial burden on people who experience this condition after TBI. Its severity is linked to injury characteristics and age, and individuals with post-traumatic epilepsy face more complex care needs than those with either epilepsy or TBI alone (Pugh). • Up to 25-30% of adults with persistent TBI symptoms at one year after TBI may have pituitary hormone deficiencies. Symptoms may be misattributed or dismissed, contributing to underdiagnosis of hypo- pituitarism. Proper endocrine evaluation is critical, as appropriate replacement can reverse symptoms due to hormone deficiencies, sig- nificantly improving cognition, mood, physical health, and quality of life (Wexler). • TBI is a significant risk factor for such cardiovascular comorbidities as hypertension and coronary artery disease. Incidence is high even in the young TBI patients of the 18–40 years age group compared to an uninjured group, warranting awareness, screening, and strategies for long-term management (Izzy). PREPUBLICATION COPY—Uncorrected Proofs 

TBI AS A CHRONIC CONDITION 11 • TBI increases dementia risk by 71 percent and is associated with multiple and often co-occurring underlying neuropathologies includ- ing both Alzheimer’s disease and non-Alzheimer’s disease pathologies. Addressing modifiable TBI comorbidities may help prevent or delay cognitive decline, and adapting emerging dementia diagnostics to post-TBI contexts is urgently needed (Gardner). • Comorbidities can emerge or persist years after TBI, and treatable conditions such as depression and pituitary hormone deficiencies can be overlooked because their symptoms resemble those of TBI. Lon- gitudinal monitoring and personalized assessments, including bio- marker tools, are key to improving diagnostic accuracy and care (Bombardier, Gardner, Izzy, Pugh, Wexler). • Targeted interventions for TBI symptoms, even when initiated years after injury, can yield significant functional gains, particularly when designed to restore host function and applied in appropriately inten- sive care or rehabilitation settings (Ashley, Loane). NOTE: This list is the rapporteurs’ summary of points made by the individual speakers identified, and the statements have not been endorsed or verified by the National Academies of Sciences, Engineering, and Medicine. They are not intended to reflect a consensus among workshop participants. The first aim of the workshop was to describe the evidence for charac- terizing traumatic brain injury (TBI) as a chronic condition. Presentations and discussions over three sessions explored epidemiological data on the incidence and prevalence of long-term symptoms, the biological mecha- nisms underlying lasting health effects after TBI, and the symptoms and co-occurring health conditions associated with TBI as a chronic condition over the life course. EPIDEMIOLOGY OF TBI AS A CHRONIC CONDITION Kristen Dams-O’Connor, professor of rehabilitation and human per- formance and director of the Brain Injury Research Center of Mount Sinai, introduced and moderated the first of these sessions, which discussed data on the risks of increased mortality and long-term sequelae associated with TBI and what is known about biological and sociodemographic character- istics associated with an elevated risk of chronic TBI. TBI is increasingly being recognized not merely as an acute event but as a chronic condition with wide-ranging and long-lasting implications across cognitive, emotional, and physical domains, as well as an array of associated comorbidities, Dams-O’Connor said. The session served to PREPUBLICATION COPY—Uncorrected Proofs 

12 EXAMINING TBI AS A CHRONIC CONDITION highlight emerging scientific evidence that supports this conceptualization, including how both injury-specific and individual characteristics contribute to the long-term trajectory of recovery or decline. For many individuals, symptoms may linger indefinitely, worsen with time, or even reemerge years after the original injury, underscoring a pattern that mirrors other chronic illnesses, she said. The current health care model often falls short by declaring recovery at the point of stabilization or plateau, thereby ending care prematurely, Dams-O’Connor continued. However, many TBI survivors continue to improve, or can develop new or worsening conditions, well beyond those early stages. A growing body of research is shedding light on who benefits from continued rehabilitation and what types of care are most effective over time, she said. She highlighted the role of a proactive approach not only to enhance long-term outcomes but also to prevent avoidable setbacks by addressing symptoms before they escalate. Dams-O’Connor concluded by underscoring the importance of epi- demiological data in shaping care models in the near term, as prospective longitudinal studies that collect clinical and biological data continue to mature. Epidemiological data from representative samples plays a crucial role in identifying patterns and risk factors, informing care strategies that are tailored to individual needs. As the field works to fill current knowledge gaps and overcome methodological limitations, there is renewed hope for optimizing quality of life for TBI survivors, she said. By better understand- ing who is at elevated risk and when to intervene, the health care system can develop more responsive, lifelong care pathways that address the evolving realities of living with TBI. Epidemiological Evidence of Long-Term TBI Sequelae Andrea Schneider, assistant professor at the University of Pennsylvania Perelman School of Medicine, discussed the growing body of evidence that TBI is a multisystem condition associated with long-term risks including functional disability, cognitive decline, dementia, epilepsy, cardiovascular disease, frailty, and increased mortality—highlighting the need for longi- tudinal research and a comprehensive, life-course approach to care and prevention. TBI Prevalence and Mortality Trends Traumatic brain injury poses a major public health challenge, with prevalence estimates in the United States ranging from 15 percent to 30 percent, Schneider began. A nationally representative study found that 15.7 percent of U.S. adults aged 40 and older reported a prior head injury with loss of consciousness, equating to nearly 23 million people (Schneider et al., PREPUBLICATION COPY—Uncorrected Proofs 

TBI AS A CHRONIC CONDITION 13 2018). Schneider emphasized that while TBI-related mortality was generally stable between 1999 and 2020, significant increases were observed among older adults, particularly those aged 75 and above (Shaik et al., 2024). Furthermore, individuals with a history of TBI had a twofold higher risk of long-term mortality over a median follow-up of 28 years compared to those without TBI, with mortality risk increasing in correlation with injury severity and frequency (Elser et al., 2023). Functional Disability and Cognitive Decline TBI has also been linked to persistent disability. Nearly 47 percent of individuals with a history of TBI reported at least one functional limitation, in contrast to 39 percent of those without such a history, with the most affected domains being mobility and work-related function (Schneider et al., 2021b). Using longitudinal data from the Atherosclerosis Risk in Com- munities (ARIC) study,1 a community-based cohort of nearly 16,000 adults, Schneider and colleagues demonstrated that individuals with TBI experienced cognitive decline equivalent to being 7.4 years older at baseline compared to peers without TBI. Those with multiple TBIs experienced declines compa- rable to those nearly 10 years older at baseline, highlighting the cumulative toll of repeated injuries on cognitive health (Schneider et al., 2021a). Risk of Dementia and Epilepsy Beyond cognitive impairment, TBI significantly increases the risk for neurological disorders. Individuals with TBI had a 1.4-fold increased risk of developing dementia over a median follow-up of 25 years, with risk ris- ing alongside the number of prior TBIs (Schneider et al., 2024b). Epilepsy is another critical sequela: individuals with TBI were found to be 1.9 times more likely to develop epilepsy over 11 years (Schneider et al., 2022). Nota- bly, individuals with both post-traumatic epilepsy and TBI had a threefold increased risk of developing dementia compared to those without either condition, underscoring the importance of examining the joint effect of comorbidities (Schneider et al., 2024a). Cardiovascular and Physical Health Consequences The implications of TBI extend into cardiovascular and physical health, as well. Using an administrative dataset of over 600,000 veterans receiving health care in the Department of Veterans Affairs (VA) system, TBI was 1 More information about the Atherosclerosis Risk in Communities study is available at https://www.nhlbi.nih.gov/science/atherosclerosis-risk-communities-aric-study (accessed April 5, 2025). PREPUBLICATION COPY—Uncorrected Proofs 

14 EXAMINING TBI AS A CHRONIC CONDITION associated with a 1.7-fold increased risk of stroke (ischemic or hemor- rhagic) over 5 years, with elevated risk persisting for more than a decade (Figure 2-1; Schneider et al., 2023). Findings from ARIC data supported this, showing a 1.3-fold higher risk of ischemic stroke in individuals with TBI, particularly among those with repeated or severe injuries (Elser et al., 2024). Additionally, individuals with TBI had a 1.7-fold increased risk of injurious falls requiring hospitalization over 23 years (Hunzinger et al., 2023) and were more likely to be prefrail or frail at baseline and to develop frailty over time (Hunzinger et al., 2024). FIGURE 2-1 TBI is associated with 1.7 times the risk of any stroke (ischemic or hemorrhagic) in U.S. military veterans over a median of 5 years, along with elevated risks for ischemic stroke and for hemorrhagic stroke over time. SOURCE: Presented by Andrea Schneider, March 11, 2025. From Schneider et al., 2023. PREPUBLICATION COPY—Uncorrected Proofs 

TBI AS A CHRONIC CONDITION 15 Research Gaps Epidemiological data supports the recognition of TBI as a chronic condition because of its wide-ranging and long-term sequelae, Schneider summarized. However, she noted that most studies focus on TBI as an isolated risk factor. She advocated for future research to address how TBI interacts with comorbid conditions, such as epilepsy, vascular disease, and frailty, and how both preinjury and postinjury factors influence outcomes across the life course. She also emphasized the need to identify high-risk subpopulations by examining medical comorbidities and social and envi- ronmental determinants of health and to target modifiable risk factors such as hypertension, diabetes, and smoking for prevention and intervention. Using Longitudinal Data and Methodological Considerations To advance TBI research, Schneider recommended using large-scale longitudinal datasets such as ARIC for deeper insights. She acknowledged that while cost-effective, this approach entails navigating methodological challenges, including missing data, repeated measures, and study attrition. Nonetheless, such datasets enable researchers to evaluate TBI as a chronic, multisystem condition and to explore its cascading effects on cognition, physical health, and comorbidity-driven risks. Schneider concluded that a comprehensive, life-course approach—incorporating medical, social, and environmental dimensions—is essential to improving outcomes and care strategies for individuals with TBI. Evidence from the TBI Model Systems National Database Angelle Sander, professor at Baylor College of Medicine, presented findings from the Traumatic Brain Injury Model Systems (TBIMS) National Database, a 35-year longitudinal study tracking individuals with mod- erate to severe TBI who received Level 1 trauma care and specialized rehabilitation. This national dataset provides detailed insights into long- term outcomes across physical, cognitive, social, and emotional domains (Dams-O’Connor et al., 2023b) (see Box 2-1). TBIMS data confirm that individuals with TBI frequently experience persistent or evolving impair- ments even decades postinjury. Functional trajectories are dynamic, and patients may show recovery followed by decline, she said, emphasizing that early improvement does not guarantee long-term stability. Functional and Cognitive Outcomes Over Time Functional change after TBI is more common than stability, Sander highlighted. A subset of TBI survivors showed improvement in functioning PREPUBLICATION COPY—Uncorrected Proofs 

16 EXAMINING TBI AS A CHRONIC CONDITION BOX 2-1 Factors Affecting Outcomes in Chronic TBI As described by Sander, longitudinal data on individuals with moderate to severe traumatic brain injury participating in the Traumatic Brain Injury Model Systems program was collected through structured interviews and assessments during inpatient rehabilitation and follow-ups, to provide insights into long-term outcomes after TBI in this population and the multiplicity of associated risk and protective factors across various domains. Selected findings are briefly summa- rized below; for additional information see Dams-O’Connor et al., 2023b: • Functional disability: Risk factors included greater acute disability, older age, and presence of comorbidities, while protective factors included better overall health, insurance coverage, and availability of support services. • Mood: Risk factors for depression and other chronic psychiatric symp- toms after traumatic brain injury included being middle age at the time of injury, experiencing post-traumatic epilepsy, unemployment, low income, and anxiety or depression one year post-injury, while protective factors included participation in religious services and resilience or strong coping ability. • Substance Use: Risk factors included pre-injury substance misuse; un- employment; younger age; male sex; and lifetime history of two or more TBIs. • Rehospitalization or reinjury: Risk factors for rehospitalization included severe or penetrating injury and seizures, while risk factors for reinjury included younger age and substance misuse. • Mortality: Risk factors included older age; male sex; education ending before high school; unemployment at time of injury; not being discharged home after injury; and difficulty walking or feeding. • Low Community Participation: Risk factors included experiencing de- pression or persistent fatigue; and characteristics of the surrounding neighborhood such as unemployment rate, housing age, and racial/eth- nic composition. Protective factors included higher cognitive function, strong caregiver and family functioning, and availability of state-level TBI services. • Marital/Relationship Stability: Protective factors included female sex, older age, non-violent injury, and absence of substance misuse. • Unemployment: Risk factors included experiencing depression or belong- ing to a racial or ethnic minority group, while protective factors included younger age at injury, higher education, pre-injury employment, male sex, being married, less severe and non-violent injury, and greater functional independence. Source: Presented by Angelle Sander, March 11, 2025, drawing on information from Dams- O’Connor et al., 2023b. PREPUBLICATION COPY—Uncorrected Proofs 

TBI AS A CHRONIC CONDITION 17 up to 10 years postinjury, with the most improvement seen early after injury. More than half of the individuals who survived their injuries were moderately to severely disabled at 5 years postinjury (Corrigan et al., 2014), and decline was common 5–10 years postinjury (Pretz and Dams- O’Connor, 2013). Physical improvements typically plateau earlier, whereas cognitive improvements can continue into the 5-year mark. Decline early postinjury is often linked to psychiatric conditions and poorer initial health, while later decline correlates with chronic medical issues (Kumar et al., 2020; Malec et al., 2019). Encouragingly, even individuals initially unable to follow commands often achieve self-care independence by year 10 (Ham- mond et al., 2019; Whyte et al., 2013), though many still function below normative cognitive levels, with 22–50 percent scoring below the third percentile at 5 years (Dams-O’Connor et al., 2018). Comorbidities, Mental Health, and Risk of Reinjury Sander highlighted that at least half of individuals with TBI are rehos- pitalized within 5 years, and 8 percent suffer another TBI, mostly within the first year (Corrigan, 2014). Comorbid conditions such as hyperten- sion, respiratory issues, diabetes, and seizures are prevalent throughout recovery. Mental health is a critical concern: 25 percent of survivors meet criteria for major depressive disorder even 2 decades later, and within 5 years, 3 percent attempt suicide and an additional 8 percent report suicidal ideation (Dams-O’Connor et al., 2023b). These data underscore the endur- ing psychiatric burden of TBI and the need for sustained behavioral health interventions, she said. Social, Vocational, and Substance Use Challenges Participation in work, education, and community life is often affected after TBI. Employment rates hover between 53–60 percent through year 5, and gains in productive activity from years 2 to 5 often reverse by year 10 (Dams-O’Connor et al., 2023b). Between 36–41 percent report dissatisfac- tion with life,2 a figure that remains stable over time (Dams-O’Connor et al., 2023b). Substance use, particularly alcohol and illicit drugs, resurfaces postinjury as individuals regain mobility and community access, with 17 percent reporting problem alcohol use and 12 percent illicit drug use at year 2 In comparison, a study using data from the 2021 National Health Interview Survey of civilian noninstitutionalized adults found that approximately 5 percent reported life dis- satisfaction, with those reporting poor physical health, psychological distress, very low food security, and some other physical, social, emotional, and financial characteristics reporting greater levels of life dissatisfaction (Miller et al., 2023). PREPUBLICATION COPY—Uncorrected Proofs 

18 EXAMINING TBI AS A CHRONIC CONDITION 5 (Dams-O’Connor et al., 2023b). These findings highlight the complex reentry challenges TBI survivors face, especially when underlying substance use histories are involved. Additional Considerations Sander emphasized that the risk of better or worse TBI outcomes dif- fers across demographic and psychosocial lines. For example, individuals at elevated risk for chronic poor outcomes include older adults, those with early disability, and individuals with substance use histories. Young adults with functional independence may paradoxically be more vulnerable to risky behaviors, reinjury, and premature mortality, she noted. Other influ- encing factors include coexisting health conditions, fitness levels, access to care, and social support. Given the interplay of these diverse factors, Sander called for a holistic, bio-psychosocial-ecological approach to TBI manage- ment (Dams-O’Connor et al., 2023b; NASEM, 2022). Gaps in Rehabilitation Access and the Need for Broader Research Despite the value of TBIMS data, fewer than 15 percent of individuals with moderate to severe TBI in the United States receive inpatient reha- bilitation, and many do not receive Level 1 trauma care, she said. Sander pointed to the need for systematic, community-based studies on those out- side the specialized care system, as their outcomes after TBI may be worse or more variable. Understanding how different outpatient or postacute services affect recovery could inform equitable, evidence-based care strate- gies, she emphasized. Ultimately, recognizing TBI as a chronic condition and expanding research beyond specialized cohorts will be essential to bet- ter address the long-term needs of all individuals affected by brain injury, she added. Discussion During discussion, Dams-O’Connor, Schneider, and Sander were joined by John Corrigan from the Ohio State University. The panel explored research gaps and considerations to gain a more comprehensive understand- ing of TBI as a chronic condition and develop an evidence-based approach to addressing it. A Need for Life-Course and Preinjury Data in TBI Research A point emphasized by all four panel members was the need for a life-course approach to understanding TBI. Schneider highlighted the PREPUBLICATION COPY—Uncorrected Proofs 

TBI AS A CHRONIC CONDITION 19 importance of collecting robust preinjury data to assess how existing comorbidities influence recovery. Corrigan echoed this by advocating for longitudinal population-based studies, such as the Adolescent Brain Cogni- tive Development (ABCD) study of youth aged 10–20 years and the ARIC cohort, which can track developmental and aging-related changes over time. Research has shown that brain injuries sustained at different devel- opmental stages, particularly early childhood or adolescence, may have distinct effects (Sariaslan et al., 2016). Moreover, TBI in older adults may serve as a sentinel event, often leading to loss of independence. The panel- ists noted the importance of longitudinal studies that follow individuals before and after injury to understand differences among individuals and corresponding effects on the injury over time, illuminating the full complex- ity of TBI as a chronic condition Methodological Challenges and Representative Sampling Panelists discussed the issue of representativeness in TBI studies, with Corrigan noting the underrepresentation of women in TBI research as an important issue. Harris, Schneider, and Corrigan described a need for adequately powered studies to explore sex-related differences in outcomes after TBI. Limited studies exploring sex differences in TBI indicate that these differences can be significant, said Harris. Sex differences are observed with other chronic diseases, and TBI is not likely to be immune from these differences, Harris said. Many studies also exclude people who never sought care or received a diagnosis, said Dams-O’Connor, thereby introducing selection bias and systematically excluding those who may be at greatest risk for poor outcomes. The panelists called for greater community-based research and enhanced recruitment strategies that capture the populations not well reflected in current clinical datasets. Self-Report and Standardization Efforts Because many individuals with TBI never receive formal medical care, self-report remains essential, the panelists said. Sander noted findings from studies in which individuals with severe TBIs, including those with cra- niotomy scars, were unaware they had sustained a brain injury owing in part to a lack of postacute care and education. Schneider and Corrigan emphasized the development and validation of retrospective self-report tools and the importance of public education to improve self-recognition of TBI symptoms. Corrigan also highlighted the importance of developing agreed case definitions and classification standards, particularly for effective medical record abstraction. Improved TBI ascertainment algorithms for use in medical records could increase granularity of data on those with TBI, PREPUBLICATION COPY—Uncorrected Proofs 

20 EXAMINING TBI AS A CHRONIC CONDITION Dams-O’Connor agreed, given that self-report data on care received often lacks the level of detail included in medical records. While prospectively gathered data is ideal, the four panelists identified retrospective self-report as a legitimate and necessary method, especially when combined with other data sources such as hospital records, Medicare data, and existing longitu- dinal studies like ARIC and the All of Us research program. Using and Harmonizing Existing Datasets and Enhancing International Collaboration Panelists emphasized the cost and time involved in launching new pro- spective studies and encouraged using existing ones. Schneider explained that studies such as ARIC and All of Us, which already collect medical and self-report data, can be enhanced with standardized TBI screening instru- ments. Corrigan added that harmonizing TBI definitions and measurement across studies would improve comparability. International collaborations, particularly with countries that have national health registries such as those in Scandinavia and New Zealand, were noted as promising opportunities. Corrigan and Schneider highlighted the value of these registries, which can link TBI data with outcomes such as employment, independence, and criminal history, although noting that registry data typically do not include individuals who never sought care. CDC studies suggest that fewer than 5 percent of adult TBIs are treated in emergency departments, highlighting the limitations of relying solely on medical records, they said. Dams-O’Connor reaffirmed the need for a complementary mix of medical, self-report, and community-sourced data for a more accurate and inclusive understanding of TBI. Schneider also emphasized that low- and middle-income countries are largely absent from global TBI research. Panelists supported current efforts to urge the World Health Assembly to recognize TBI as a chronic and notifiable condition, to encourage broader data collection beyond countries with national registries. Mechanisms of Injury and Cumulative Effects The conversation broadened to include the need for more precise char- acterization of injury mechanisms. Corrigan emphasized that TBI is often not a single event, but rather a cumulative series of exposures that occur across the life span. Military veterans, for instance, may experience simul- taneous blast and blunt-force injuries. Dams-O’Connor pointed out that different injury mechanisms, such as hypoxic injury caused by strangulation in intimate partner violence (IPV) or repetitive concussions in sports, may have different long-term outcomes (Dams-O’Connor et al., 2023a). Under- standing how biomechanics and injury characteristics influence long-term PREPUBLICATION COPY—Uncorrected Proofs 

TBI AS A CHRONIC CONDITION 21 symptoms requires refined measurement and comprehensive injury profiles. Corrigan highlighted the effort through the National Institute of Neurologi- cal Disorders and Stroke (NINDS) to develop the new Clinical, Biomarker, Imaging, plus Modifier (CBI-M) approach to classifying TBI as a promising framework for capturing injury characteristics and modifiable risk factors (Manely et al., 2025). Embracing Complexity and Future Research Directions The session concluded with a consensus that TBI research must move beyond overly simplistic models. Dams-O’Connor warned that focusing solely on “index injuries” (e.g. the initial brain injury that takes place in a given context) neglects the complexity of lifetime exposures. Schneider and Sander reiterated the importance of accounting for social and environmen- tal determinants, comorbidities, and functional diversity in outcomes. For example, Corrigan and Dams-O’Connor emphasized the need for safe and effective screening for TBI in domestic violence shelters, while cautioning against the potential misuse of such data in legal contexts such as child custody disputes. Corrigan called for broader use of the CBI-M framework and emphasized the need to understand injury context, timing, and cumula- tive burden. Collectively, the panel called for multidisciplinary, longitudinal research that reflects the multifactorial reality of living with TBI. Only by embracing this complexity can researchers, clinicians, and policy makers develop interventions that meaningfully improve long-term outcomes for people with TBI, she said. NEUROPATHOPHYSIOLOGICAL MECHANISMS UNDERLYING TBI AS A CHRONIC CONDITION Amy Wagner, professor and vice chair in the department of physical medicine and rehabilitation at the University of Pittsburgh, introduced and moderated the next session, which explored the biological basis for chronic TBI and identified research gaps and barriers to advancing understanding of lasting health effects. This session and the following session on health outcomes and comorbidities included clinical and technical discussions of changes in the brain and immune system after TBI. As discussed by the speakers, research shows that TBI can accelerate brain aging, increase risk for neurodegenerative diseases such as Alzheimer’s disease, and contrib- ute to concerns such as depression, epilepsy, and chronic pain. Speakers described how an important driver of long-term effects after TBI is ongo- ing brain inflammation and disrupted communication between brain and body systems, which can leave people more vulnerable to infections and other health problems even years after injury. Studies suggest that targeting PREPUBLICATION COPY—Uncorrected Proofs 

22 EXAMINING TBI AS A CHRONIC CONDITION inflammation, including from brain immune cells called microglia. may improve recovery even long after the initial injury. Session speakers also emphasized that TBI treatment, rehabilitation, and monitoring need to be tailored to the person’s symptoms and stages of recovery. TBI as a Chronic Neurological Condition David Loane, neuroimmunologist and associate professor at Trinity College Dublin, provided an overview of the chronic neuropathology of TBI, the contributions of chronic inflammation to neuropathology, the communication between central nervous system (CNS) and peripheral sys- tems in the context of systemic inflammation, associations between TBI and changes in the host immune response, and the risk those immune response changes pose in terms of secondary complications and mortality. Loane emphasized the complex and chronic nature of TBI, underscoring that both repetitive mild TBIs and single severe TBIs can lead to neurodegenerative diseases such as Alzheimer’s disease (AD) and chronic traumatic encepha- lopathy (CTE). These injuries are associated with long-term outcomes including hippocampal atrophy (a region of the brain associated with mem- ory and cognitive function), executive dysfunction, psychiatric symptoms (e.g., depression, anxiety, aggression), post-traumatic epilepsy, and chronic pain. These effects highlight the enduring nature of TBI and challenge the outdated view that it is a short-term or static condition, he said. Accelerated Brain Aging and Cognitive Impairment Loane discussed evidence for the hypothesis that TBI accelerates brain aging. Using the Alzheimer’s Disease Neuroimaging Initiative (ADNI) data- base and machine learning, researchers demonstrated that TBI patients had a predicted brain age 4.66 years (gray matter) to 5.97 years (white matter) older than their chronological age (Cole et al., 2015). This accelerated aging was predictive of cognitive impairment and suggests that TBI pushes individuals closer to the threshold for age-related neurodegeneration (Smith et al., 2013). The work supports the notion that TBI disrupts the natural aging trajectory of the brain. Neuropathological Mechanisms of Chronic TBI Loane provided a detailed overview of neuropathological features linked with chronic TBI. These include amyloid beta accumulation, tau tangles, axonal degeneration, TDP-43 aggregation, and cerebrovascular pathology (Dams-O’Connor et al., 2023b; Emrani et al., 2025; Sandsmark et al., 2019). These changes are highly heterogeneous, reflecting differences PREPUBLICATION COPY—Uncorrected Proofs 

TBI AS A CHRONIC CONDITION 23 in injury severity and mechanism. For instance, repetitive mild TBI may preferentially result in sulcal tau pathology and frontotemporal involve- ment, while severe TBI may involve diffuse axonal injury and white matter loss. The Role of Chronic Neuroinflammation Central to the chronic effects of TBI is sustained neuroinflammation. Loane highlighted microglia and astrocytes—the brain’s innate immune cells—as key players. Chronic microglial activation persists postinjury and contributes to neurodegeneration, he said (Loane et al., 2014). PET imag- ing has shown long-term thalamic inflammation in TBI survivors 17 years postinjury (Ramlackhansingh et al., 2011), with evidence of hippocampal sclerosis and white matter degeneration (Johnson et al., 2013). Aging com- pounds this issue through “inflammaging,” a state of heightened immune responsiveness and cellular senescence (Scheiblich et al., 2020). Microglia as Therapeutic Targets Loane shared data from rodent models showing that targeted removal of chronically activated microglia using a colony-stimulating factor 1 recep- tor (CSF1R) inhibitor led to improved motor and cognitive outcomes, and arrested chronic lesion development (Henry et al., 2020). Microglial deple- tion suppressed the expression of genes associated with Alzheimer’s-like neurodegeneration. These findings indicate that therapeutic interventions targeting microglial-mediated inflammation in the chronic postinjury period may restore brain function and halt further degeneration, he said, thereby expanding the window for effective treatment beyond the acute phase. TBI as a Systemic Disorder TBI affects not just the brain but also the peripheral immune sys- tem, Loane said, emphasizing the complex, bidirectional communication between the brain and organs such as the lungs, liver, gut, and bone mar- row. After a TBI, systemic immune responses are often triggered through the autonomic nervous system (ANS), the hypothalamo-pituitary-adrenal (HPA) axis, and peripheral organ interactions, resulting in acute immu- nosuppression and, over time, chronic immune dysregulation (Meisel et al., 2005). In both clinical and animal studies, this dysregulation affects immune cell function, including phagocytosis and inflammatory responses, and can make the immune system less capable of fighting off subsequent infections or inflammatory conditions (Hanscom et al., 2021; Ritzel et al., 2018). PREPUBLICATION COPY—Uncorrected Proofs 

24 EXAMINING TBI AS A CHRONIC CONDITION Vulnerability to Secondary Infections Data indicates that both mild and more severe TBIs cause lasting vulnerabilities in immune function, Loane said, creating vulnerability to secondary complications such as infections during the chronic phase of recovery. Loane highlighted the increased susceptibility of TBI patients to infections, especially pneumonia, which is a leading cause of mortality. Rodent models showed that TBI suppresses immune cell function in the lungs, impairing the response to pathogens like Streptococcus pneumoniae (Doran et al., 2020). Infected TBI rodents exhibited higher mortality, increased brain inflammation, and reduced cytokine responses, such as interleukin-1β. This vulnerability persisted even 60 days postinjury, suggest- ing that TBI leads to chronic immune dysfunction and hampers recovery from common infections long after the initial trauma. Exacerbated Effects from Systemic Inflammation In models where rodents were exposed to gastrointestinal inflammation via chemical colitis post-TBI, Loane shared data showing worsened motor outcomes and reactivation of autonomic dysregulation (Hanscom et al., 2021). Even mild TBI led to systemic immune impairment when challenged with secondary insults. Findings suggest that TBI induces a long-term shift in the host immune environment—first towards immunosuppression and later toward hyperinflammation. This evidence underscores the critical importance of understanding how systemic inflammation interacts with and exacerbates chronic brain injury, especially when patients face new health challenges months or years after their initial TBI. Implications for Rehabilitation and Therapy The chronic immune dysregulation observed in TBI creates opportuni- ties for late-stage interventions, Loane continued. He emphasized the need for therapies that restore immune balance and mitigate neuroinflammation, such as agents targeting NOX2 or NLRP3 inflammasomes. This perspec- tive reframes TBI management to include the long-term biological impact of brain injury, where systemic inflammation is both a consequence and a contributor to ongoing neurological damage. Rehabilitation strategies should therefore address both neural and immune recovery, he emphasized. Reframing TBI as a Chronic Disease Loane concluded that TBI should be understood as a chronic dis- ease with both central and systemic effects, where neuroinflammation and impaired immune responses play a critical role in shaping long-term PREPUBLICATION COPY—Uncorrected Proofs 

TBI AS A CHRONIC CONDITION 25 health outcomes. Chronic pathology including brain atrophy, impaired host immunity, and susceptibility to secondary infections can profoundly affect long-term health outcomes, and research focused on the integrated patho- biology of TBI is needed to improve patient care, he said. He argued that advancing an understanding of the brain–immune system interplay could reveal key intervention points to improve recovery and reduce vulnerability to secondary complications across the life span. He also emphasized the usefulness of targeted interventions for TBI symptoms even if initiated well after the initial injury, particularly when designed to restore host function. Loane emphasized that rehabilitation and pharmacologic therapies should be developed to modify underlying mechanisms of dysfunction, highlight- ing the importance of timing and personalized treatment during the chronic phase of recovery. Chronic TBI-Associated Pathology in the Context of Health, Chronic Conditions, and Function Wagner echoed the need to consider TBI as a systemic condition, high- lighting the importance of understanding the long-term effects of TBI on multiple body systems and the value of integrating biomarkers into this effort. She introduced her Rehabilomics Research model (Wagner, 2010), which aligns with calls for a broader, more holistic understanding of health, rooted in functional capacity rather than merely the absence of disease. Using the World Health Organization’s (WHO’s International Clas- sification of Functioning (WHO, 2001) as a conceptual anchor, Wagner described how biomarkers can help identify the physiological underpin- nings of functional deficits following TBI. Function, she argued, is a key indicator of health in chronic conditions like TBI, and understanding it requires analyzing how biological and environmental factors interact over time. She gave the example of cognitive impairment, one of the most debilitating outcomes after TBI, and described how her team developed an inflammatory load score that correlates early inflammatory markers with neuropsychological test results at 6 and 12 months postinjury (Milleville et al., 2020). This inflammatory load score not only predicted cognitive performance but was also associated with everyday functional outcomes like independence and quality of life, Wagner said. She further highlighted how biomarkers can be used to better under- stand outcomes in TBI populations. Her team is mapping relationships among inflammatory and autoimmune markers, neuronal damage indi- cators such as the biomarker neurofilament light (NfL), and cognitive outcomes at 6 months postinjury. The analysis reveals connections among autoantibodies, inflammation, and cognitive impairment that form a com- plex biological network affecting recovery and help to identify potential therapeutic targets. This integrative approach is being extended to study PREPUBLICATION COPY—Uncorrected Proofs 

26 EXAMINING TBI AS A CHRONIC CONDITION active drivers of secondary conditions like microglial health, autophagy, and cellular senescence in collaboration with other researchers, she said. Looking ahead, Wagner proposed that biomarker technologies could become scalable tools for monitoring chronic TBI in community settings. Coupled with telehealth platforms and point-of-care diagnostics, these tools could help track biological dysfunction in real time and offer personalized treatment recommendations. She concluded by suggesting that such inno- vations hold promise not just for research but for improving long-term recovery and daily life for individuals living with chronic effects of TBI. Panel Discussion Insights from Preclinical TBI Research Wagner opened the discussion by asking about the limitations of rodent models in studying chronic TBI, specifically the challenge of translating rodent life spans to human conditions. Loane acknowledged these limita- tions but argued that rodent models offer unique opportunities to inves- tigate genetic and inflammatory mechanisms over time that cannot be explored in humans. He emphasized the advantages of knowing both the timing of induced injury and the assessment window in experimental sys- tems. He also advocated for integrating established clinical biomarkers, such as NfL and immune-related markers, into preclinical studies. This integration would allow researchers to better align rodent outcomes with human pathologies, he said, enhancing translational relevance. Chronic Immune Dysfunction and Comorbidities Wagner shifted the focus to chronic immune dysfunction and its role in secondary conditions such as epilepsy, depression, and fatigue that can arise months or years post-TBI. Loane highlighted interleukin-1 (IL-1) as a central immune mediator linking astrocytic and microglial activation to altered brain wiring, particularly in post-traumatic epilepsy. While complex conditions like frailty may be harder to model in rodents, he said, the use of biomarkers through blood assays or molecular imaging can help to identify overlapping mechanisms across comorbidities. This approach could help identify targets for individuals with treatment-resistant epilepsy and sup- port the development of translational interventions, he suggested. Cellular Aging, Senescence, and Treatment Targets Wagner asked about cellular aging and senescence in older adults with TBI. Loane critiqued the blunt nature of steroid treatments that PREPUBLICATION COPY—Uncorrected Proofs 

TBI AS A CHRONIC CONDITION 27 indiscriminately suppress immune function, arguing instead for more pre- cise, mechanism-based drugs that modulate metabolism, cytokine signaling, and cell-specific pathways. Loane also highlighted the regenerative role of anti-inflammatory cytokines such as IL-10, brain-derived neurotrophic factor, and nerve growth factor in promoting neural repair. He emphasized the importance of administering treatments at the correct time, saying that while microglia and astrocytes serve beneficial roles in the acute phase by clearing debris, their chronic activation can lead to neurodegeneration if left unchecked. Timing and Tailored Interventions Expanding on the role of timing, Loane suggested that different phases of TBI recovery might require different therapeutic strategies. For example, early postinjury interventions could focus on the modulation of autophagy to support cellular cleanup, while later stages might benefit from rehabilita- tion and exercise. Preclinical models allow for the testing of such sequenced interventions, he noted, especially when paired with pharmacodynamic bio- markers that track changes in neurodegeneration and inflammation. Loane challenged the idea there is only a narrow treatment window postinjury, emphasizing that TBI can be addressed as a lifelong condition with oppor- tunities for intervention throughout the chronic phase. Sex Differences in Biological Responses After TBI Wagner raised the issue of sex differences in TBI-related outcomes and the underrepresentation of females in preclinical brain injury research. Loane agreed that work has historically focused on male responses. Emerg- ing data show significant sex-based differences in baseline immune function and responses to injury, he said, such as higher IL-1 levels and distinct immune receptor expression in females. While females may exhibit some protective effects in the acute phase, aging can lead to worsened inflam- matory responses and outcomes, especially postmenopause. These find- ings highlight the importance of studying hormonal differences to develop more personalized and effective treatments for both male and female TBI survivors. Translation of Preclinical Research to Human Therapies Throughout the discussion, Loane and Wagner emphasized the need to operationalize these preclinical insights into human clinical trials and to develop personalized, phase-specific interventions grounded in mechanis- tic understanding and supported by translational biomarkers. The use of PREPUBLICATION COPY—Uncorrected Proofs 

28 EXAMINING TBI AS A CHRONIC CONDITION biomarkers to bridge preclinical and clinical research could facilitate drug repurposing and personalized therapies, Loane suggested. Wagner added that behavioral models in rodents, when aligned with the inflammatory hypothesis of depression, could provide translational potential for treating neuropsychiatric sequelae of TBI. The dialogue highlighted how rodent models, when used thoughtfully and with clinically relevant markers, can inform the design of therapeutic interventions that address the full arc of TBI injury, recovery, and comorbidity. EVIDENCE ON HEALTH OUTCOMES AND COMORBIDITIES The third session explored outcomes and comorbidities linked to TBI, focusing on depression, post-traumatic epilepsy, endocrine dysfunction, cardiovascular disease, and dementia. The session was introduced and moderated by Jeanne Hoffman, a rehabilitation psychologist and professor at the University of Washington. Hoffman highlighted the range and complexity of the long-term effects of TBI, noting that although the session could not cover every symptom, the five areas chosen illustrate the breadth of medical and psychological challenges that individuals with chronic TBI may face. These conditions can overlap and have a compounded effect on a person’s daily function and quality of life, she added. Recognizing that these conditions influence long- term function and quality of life and identifying and addressing knowledge gaps in understanding how these conditions develop and interact over time will be key to improving treatment, prevention, and management of post- TBI outcomes, she said. Before moving to the panel, Hoffman welcomed insights from several people experiencing long-term effects from TBI (Box 2-2). Depression and TBI Charles Bombardier, clinical psychologist and professor at the Univer- sity of Washington, outlined the associations between TBI and long-term increased risk of depression and associated mental health conditions. A study found that 53 percent of 559 participants experienced a period of major depression during the 1 year period following hospitalization with TBI, constituting a rate eight times higher than that of the general popula- tion (Bombardier et al., 2010). Both TBI and individual history of depres- sion drive this rate, he said, highlighting that 43 percent of the study sample reported depression diagnosis and/or treatment prior to TBI. Whereas 41 percent of individuals with no history of depression experienced an epi- sode of depression during the first year after TBI, this figure rose to 69 percent for individuals with a prior history of depression and 73 percent PREPUBLICATION COPY—Uncorrected Proofs 

TBI AS A CHRONIC CONDITION 29 BOX 2-2 Perspectives of Individuals Living with Chronic TBI Symptoms The session featured a video in which three individuals living with TBI de- tailed the lasting effects of their injuries. Carole Starr, founder and facilitator at Brain Injury Voices and Brain Injury Association of America (BIAA) Advisory Council cochair, stated she experiences multiple, varied long-term TBI symptoms. Despite trajectories such as hers, many people with TBI are told that their experi- ences are “all in their head,” said Starr. Moreover, people often have a hard time understanding the magnitude of TBI symptoms. Starr said that upon sharing her memory issues or fatigue, people often reply that they too have that experience, not understanding the difference in severity at play. Jack Somers, Lived Experi- ence Veteran Advisor at the Department of Veterans Affairs Southwest Region Epilepsy Centers of Excellence, remarked that his TBI went undiagnosed for over a decade. During this time, he experienced post-traumatic epilepsy, anxiety, depression, mood swings, insomnia, memory loss, and impaired executive func- tioning and communication skills. He described that his difficulty communicating, understanding relationships, and managing a schedule were particularly challeng- ing for his friends and family to navigate. Underscoring the tendency of doctors to work in silos, Somers said that his TBI symptoms were treated as separate conditions. Kelly Lang, BIAA Advisory Council cochair, stated that TBI is an invis- ible disability and locating effective care can be challenging. She described that finding effective medication for her daughter’s TBI-related migraines took years. Medications are not equally effective for everyone, and it is important to honor the pain that people with TBI experience, said Lang. Stating that some changes in the TBI field have occurred since she and her daughter were injured 23 years ago, Lang stated that she has spoken with families contending with more recent TBIs, and too often they are told by care providers that they are “good to go.” Lang encouraged individuals with TBI to continue the search for care until they locate a doctor who empathizes and works to solve the issues they are facing. Starr remarked that TBI is similar to diabetes or heart disease in that it involves daily symptoms. She urged viewers to understand the fluctuating nature of these symptoms and to refrain from judging people with TBI based on whether they are able to perform tasks. Somers explained that the term blast radius is used in the military to describe the destructive power of an explo- sive device. He stated that the blast radius of TBI will continue to be truly devas- tating until care providers and researchers understand more about the condition. for individuals experiencing depression at the time of injury. These findings indicate the importance of assessing TBI patient psychiatric history and screening for depression, Bombardier emphasized. Bombardier highlighted research from Alway and colleagues that tracked 160 individuals with TBI and conducted diagnostic assessments of psychiatric disorders for 5 years postinjury (Alway et al., 2016). People with TBI are at elevated risk for a variety of neuropsychiatric conditions PREPUBLICATION COPY—Uncorrected Proofs 

30 EXAMINING TBI AS A CHRONIC CONDITION with rates gradually declining over time (see Figure 2-2 from Howlett et al., 2021, developed using data from Alway et al., 2016). Bombardier par- ticularly noted that rates of mood disorders ranged from approximately 40 percent 1 year postinjury to 30 percent over the 5-year period, indicating a sustained effect of TBI on depression, he said. Delving into the risk of depression after TBI, he reported that a study tracking patient data on over 4,000 individuals with TBI for 10 years postinjury found higher rates of depression compared to a similar sample with no TBI (Izzy et al., 2022). Emphasizing that this study excluded participants with a prior history of depression or TBI, Bombardier under- scored that approximately 20 percent of individuals with mild TBI and 15 percent of individuals with moderate to severe TBI experienced depres- sion compared to 5 percent of people with no history of TBI. Moreover, a long-term study of U.S. veterans demonstrated that risk of depression remains elevated for 50 years after TBI (Holsinger et al., 2002). The study compared a half century of records for approximately 1,000 World War II veterans hospitalized for nonpenetrating brain injuries and 1,000 veterans FIGURE 2-2 Prevalence of psychiatric disorders during the first 5 years after TBI. NOTE: The prevalence of mood, anxiety, and substance use disorders (SUD) were assessed over 5 years of follow-up in a study of people who experienced moder- ate to severe TBI, indicating a sustained risk of such disorders beyond the acute recovery phase. SOURCE: Presented by Charles Bombardier, March 11, 2025. From Howlett et al., 2021. PREPUBLICATION COPY—Uncorrected Proofs 

TBI AS A CHRONIC CONDITION 31 hospitalized for nonhead injuries. After controlling for demographic and health factors, researchers found that 18.5 percent of veterans with head injury demonstrated a lifetime history of major depression, compared to 13.4 percent of veterans with no head injury. The rate of current major depression at 50 years postinjury was 11.2 percent for veterans with head injury and 8.5 for those with no head injury. Bombardier emphasized that the increased risk of depression in individuals with TBI lasts a lifetime. Risk of depression carries risk for associated conditions, Bombardier explained. For example, evidence indicates that depression can negatively affect cognitive impairment, insomnia, chronic pain, and functioning in social, recreational, and work settings (Andelic et al., 2018; Del Pozzo et al., 2024; Fann et al., 1995; Gomez-Hernandez et al., 1997; Hoge et al., 2008; Izzy et al., 2022; Kishi et al., 2001; Kumar et al., 2018; Rao et al., 2014; Rapoport et al., 2005; Satz et al., 1998; Teasdale and Engberg, 2001; Uiterwijk et al., 2022; Wickwire et al., 2023). Understanding relationships among conditions associated with depression offers new approaches for treating depression in individuals with TBI, he suggested. For example, a study of collaborative care treatment for chronic pain in people with TBI revealed improvements in both chronic pain and depression (Hoffman et al., 2024). Interventions to improve psychosocial, recreation, and work functioning also improved symptoms of depression (Bombardier et al., 2009). He concluded that treating conditions that contribute to depression could be an effective approach to improving depression in individuals with TBI. Post-Traumatic Epilepsy Mary Jo Pugh, professor of internal medicine and population health at the University of Utah, discussed the prevalence, complex comorbidity, and challenges associated with post-traumatic epilepsy (PTE). Defined as a recurrent seizure disorder occurring after TBI, PTE accounts for approxi- mately 20 percent of symptomatic cases of epilepsy (Yu, 2021). Research indicates that the prevalence of epilepsy is higher in both civilian and mili- tary populations with TBI than in the general population. However, while estimates of PTE in civilians range from 2 to 20 percent, incidence increases to between 22 and 53 percent in the military population, she noted, attrib- uting this in part to the severity of injuries sustained in combat (Annegers et al., 1998). Indeed, TBI severity is a primary risk factor for PTE, Pugh said, with increased risk for individuals who experience penetrating injury, longer periods of loss of consciousness, or longer gaps in memory. The likelihood of developing PTE after a penetrating head injury is approximately 50 percent (Pugh et al., 2021). Other characteristics associ- ated with severe TBI, such as prolonged coma, intracranial bleeding, and PREPUBLICATION COPY—Uncorrected Proofs 

32 EXAMINING TBI AS A CHRONIC CONDITION seizures within a week of injury, are strong predictors of PTE. Research suggests that individuals with mild TBI are at a slightly higher risk of developing PTE than those with no history of TBI, she indicated. Pugh explained that while this risk is modest—at about 1.5 percent—it translates to a large number of people at the population level, given the large number of people who experience mild TBI. The risk of PTE is highest for people who are very young or very old. Although the risk of PTE is highest in the first 2 years after injury, it can occur 10–20 years or more after TBI, Pugh indicated. Complex Comorbidity in PTE PTE is associated with mental health, neurocognitive, and psychosocial issues and with neurological and chronic disease, Pugh described. Treat- ment resistance to medications and procedures for recurrent seizures is more common among individuals with PTE than those with epilepsy alone. Common side effects of antiseizure medications include dizziness, fatigue, and memory problems. Given that people with PTE are more likely to take multiple medications to control seizures, she said, an increased medication regimen can magnify these side effects. Pugh underscored the importance of early diagnosis and treatment for PTE to mitigate the long-term effects of treatment resistance. Seizures can involve falls and injuries, creating vulnerability to addi- tional TBIs. Moreover, TBI comorbidities can become more complex with PTE, she noted. For example, people with TBI have a higher risk of depres- sion, a risk that is compounded in people with PTE. Similarly, anxiety, bipolar disorder, schizophrenia, post-traumatic stress disorder (PTSD), irritability, sleep disorders, suicidal ideation, and suicide attempts and completions are more common in people with PTE than in those with TBI alone, she reported. Recurrent and difficult-to-control seizures are associ- ated with subsequent neurocognitive conditions such as memory problems, difficulty concentrating, slow processing speed, mild cognitive impairment, and dementia, said Pugh. Recent studies have found that epilepsy and PTE are associated with the emergence of neurological and other chronic diseases, and that prior comorbidities play a role in this association, Pugh indicated. A study found that conditions including stroke, hypertension, cardiovascular disease, and diabetes emerged after epilepsy in a veteran cohort (Pugh et al., 2025). The interaction of TBI and epilepsy could create a more significant cluster of comorbidities occurring earlier in people with PTE compared to TBI alone, epilepsy alone, or controls, Pugh suggested. Moreover, the emergence of chronic disease contributes to the increased risk of mortality seen in people PREPUBLICATION COPY—Uncorrected Proofs 

TBI AS A CHRONIC CONDITION 33 with PTE in comparison with TBI or epilepsy alone or the absence of either condition, she noted. Psychosocial Challenges Pugh emphasized that complex comorbidity and treatment-resistant epilepsy have substantial effects on people with PTE and their loved ones and caregivers. For example, fear of seizures can cause effects such as social isolation and reduced physical and emotional quality of life. Noting research gaps regarding psychosocial outcomes of PTE, Pugh highlighted a study that found that U.S. military veterans with PTE had significantly lower scores for quality of life measures and quality-adjusted life years than those with epilepsy or TBI alone. Studies in the civilian sector suggest that people with PTE may have more difficulty coping and participating in activities than individuals with TBI alone. Evidence indicates that caregivers of relatives with epilepsy experience relationship strain, disruptions in work and daily routine, and mental health conditions such as anxiety, depression, and PTSD, Pugh continued. Emerging data from an ongoing study of the effects of PTE found that caregivers of people with PTE report higher levels of stress, sleep interference, and poorer health than caregivers of veterans with epilepsy or TBI alone. These findings emphasize the need for more comprehensive evaluations of social, emotional, and health outcomes for individuals with PTE and their caregivers and family members, she said. Research Gaps and Next Steps Addressing PTE requires multidisciplinary and person-centered care, Pugh contended, suggesting that clinicians should involve caregivers to the extent approved and requested by the patient to facilitate overall adherence to treatment. These caregivers also need support to maintain their health and well-being, she said. Although research on PTE treatments is ongoing, there has so far been little progress in identifying treatments that prevent or address PTE specifically, versus epilepsy generally, said Pugh. It is not yet known whether treatment for epilepsy in general will be the most effective treatment option for PTE, she added. Few longitudinal studies examine the emergence of and outcomes for PTE, and findings from the Transforming Research and Clinical Knowledge in TBI (TRACK-TBI) study on epilepsy are only beginning to emerge. Pugh emphasized the importance of longi- tudinal studies to better understand PTE comorbidities and psychosocial outcomes in the context of individuals’ medical histories. She also empha- sized the need to identify treatment strategies for PTE to enhance health and well-being for affected people and families. PREPUBLICATION COPY—Uncorrected Proofs 

34 EXAMINING TBI AS A CHRONIC CONDITION Pituitary Deficiencies After TBI: Long-Term Effects on Health and Recovery Tamara Wexler, neuroendocrinologist and professor at New York Uni- versity, discussed TBI-related chronic anterior pituitary hormone deficien- cies (post-traumatic hypopituitarism, PTHP) and their role in the health of patients after TBI. Wexler specified that deficiencies attributed to hypopitu- itarism may include hypothalamic deficiencies, and that “chronic” in this set- ting refers to deficiencies beyond at least three months. She emphasized that identification and replacement of deficient hormones is important to reverse associated symptoms, which may include cognitive, emotional, and physical effects. Numerous studies have found that PTHP occurs at higher rates after TBI in both adults and children, she said (Agha et al., 2005; Bondanelli et al., 2004; Izzo et al., 2016; Kaulfers et al., 2010; Krahulik et al., 2017; Kreber et al., 2016; Niederland et al., 2007; Personnier et al., 2014; Schneider et al., 2006; Silva et al., 2015). After accounting for appropriate evaluations and diagnostic criteria, approximately 25–30 percent of adults with persistent TBI symptoms have PTHP, Wexler said. In contrast, the prevalence of PTHP in the general population is less than 0.05 percent (Regal et al., 2001). Pituitary hormone deficiencies can develop after mild or severe TBI, said Wexler (Aimaretti et al., 2005; Alavi et al., 2016; Tanriverdi and Kele- stimur, 2015; Yang et al., 2015; Yuen et al., 2022). Moreover, PTHP can appear after a delay of months or years following the injury (Aimaretti et al., 2005; Casano-Sancho et al., 2013; Krahulik et al., 2017; Yang et al., 2015). Studies of adults and children throughout the first year after injury found that some individuals with normal hormone levels at 3 or 6 months post-TBI have a pituitary a deficiency at 12 months postinjury (Aimaretti et al., 2005; Casano-Sancho et al., 2013; Krahulik et al., 2017); recovery was also seen during this time period, though was not observed in situa- tions of panhypopituitarism (in which all anterior pituitary hormones are affected). Growth hormone deficiency (GHD) is the most frequent pituitary deficiency beyond one year post-TBI, Wexler noted; within the first year, GHD or hypogonadal hypogonadism have been most frequently reported.. Predictive Characteristics and Symptoms Given the large number of individuals who experience TBI, researchers have explored what PTHP screening criteria might predict PTHD, said Wex- ler. Neither the severity nor mechanism of injury appear to be clinically useful markers to predict of PTHP; the limited studies of specific settings of injury such as military blast injuries and recurrent sports injuries also report higher levels of injury (Baxter et al., 2013; Ciarlone et al., 2020; Kelly et al., 2014; Lee et al., 2022; Undurti et al., 2018). Imaging should not be used to rule out hormone deficiencies, as individuals with PTHP may have normal imaging results, and clinically useful biomarkers of PTHP are not currently available, PREPUBLICATION COPY—Uncorrected Proofs 

TBI AS A CHRONIC CONDITION 35 she said. Therefore, persistent symptoms after TBI or failure to recover as expected should be used as an indication to consider full pituitary evaluation. Sequelae of PTHP include physical, cognitive, and emotional effects, and symptoms may overlap with other post-TBI symptoms, she noted. Sequelae of PTHP may include changes in body composition, skin, and hair; skeletal and cardiovascular changes; executive function decrements; mental fogginess; fatigue and decreased exercise capacity; irregular periods; decreased libido; and mood changes. Moreover, untreated hypopituitarism is associated not only with decreased quality of life, but with increased morbidity and/mortal- ity and can decrease quality of life (Wexler, 2023). The Pituitary and its Functions The pituitary manages production of cortisol from the adrenal glands, thyroid hormone from the thyroid gland, estrogen and, testosterone from the ovaries and testes, respectively, , and growth hormone, Wexler explained. Located at the base of the brain, the pituitary sits in a bony saddle (the sella), and this placement can make it vulnerable to injury and neuroinflammation, she said. Wexler reported that she too often sees patients years post-TBI who have not been evaluated for PTHP despite sug- gestive of hormone deficiencies. This includes issues with executive function which may be seen in adults with acquired growth deficiency: difficulties multitasking, organization, focus, cognitive processing speed, and working memory that disrupt employment and home life. Care providers may fail to conduct GHD evaluation in adults who have reached their full height, she noted, despite the multiple functions that growth hormone carries out throughout the body including a role in executive function, cardiovascular risk factors, bone strength, body com- position, and energy and exercise capacity. Studies indicate that GHD may contribute to quality of life and neurocognitive sequalae after TBI and that individuals with TBI who have GHD fare more poorly than those with suffi- cient growth hormone levels (Kelly et al., 2014; Kreber et al., 2016). Wexler highlighted that growth hormone replacement in patients with post-TBI GHD has led to improvements in cognition, body composition, and qual- ity of life (Bhagia et al., 2010; High et al., 2010; Tanriverdi et al., 2010). Underdiagnosis of Post-TBI Pituitary Deficiencies Despite evidence of the increased risk of pituitary hormone deficiences after TBI and the harmful effects of hypopituitarism, PTHP remains underdiagnosed, said Wexler. Factors contributing to this underdiagnosis include lack of awareness among care providers, the overlap of symp- toms of PTHP and TBI, and incomplete understanding of the diagnosis of pituitary-level hormone deficiencies, she said. For example, screening PREPUBLICATION COPY—Uncorrected Proofs 

36 EXAMINING TBI AS A CHRONIC CONDITION for thyroid-stimulating hormone (TSH) is commonly conducted at annual physicals. Although this test indicates whether the thyroid gland itself is functioning normally, Wexler explained TSH alone is insufficient to diag- nose hypothyroidism due to a pituitary (or hypothalamic) cause. A feed- back loop occurs in which the pituitary produces TSH that stimulates the thyroid gland to make thyroid hormone. In cases in which the thyroid gland is unable to produce sufficient hormone, a functioning pituitary will secrete higher levels of TSH. Thus, a high TSH reading indicates hypothyroidism. However, if the pituitary or hypothalamus is not functioning properly, it cannot sufficiently increase TSH secretion and TSH will remain within the normal range. In this situation, a person with PTHP and hypothyroid- ism would have a normal TSH level and a low level of free T4 thyroxine hormone. Thus, TSH evaluation alone is insufficient in diagnosing central hypothyroidism, Wexler said. Similarly, care providers may inappropriately use IGF-1 as the sole test for GHD, without recognizing that some individu- als with GHD have normal IGF-1 levels. In women, missed periods may be misattributed to stress or early menopause without testing follicle-stimu- lating hormone which would be inappropriately normal in hypogonadism from a pituitary cause. Wexler emphasized that PTHP is an important sequela of TBI that can be diagnosed and treated. All individuals with a history of TBI who are experiencing persistent and disruptive signs or symptoms associated with pituitary deficiencies should be considered for full pituitary evaluation, she maintained, and evaluation over time may be warranted. Furthermore, care providers should offer hormone replacement therapy to individuals diagnosed with PTHP via appropriate testing, said Wexler. Long-Term Risks of Cardiovascular Diseases After TBI Saef Izzy, associate professor at Brigham and Women’s Hospital and Harvard Medical School, discussed the increased risk of developing long- term cardiovascular disease in individuals with TBI. Cardiovascular issues in TBI patients receiving acute care have been reported for more than 3 decades, Izzy noted. For instance, patients with acute TBI have developed cardiac arrythmias, myocardial injuries, and myocardial dysfunction in addition to experiencing adrenergic storms and cytokine releases (Coppalini et al., 2024; Gregory and Smith, 2012; Krishnamoorthy et al., 2017).3 3 An adrenergic storm is a sudden increase in neurotransmitters such as epinephrine and norepinephrine that can occur after TBI and certain other health conditions, producing symptoms such as high heart rate, elevated blood pressure, hyperventilation, fever or oth- ers. Cytokines are signaling molecules that affect the immune system, for example activating neuroinflammation. PREPUBLICATION COPY—Uncorrected Proofs 

TBI AS A CHRONIC CONDITION 37 Research has indicated an association of TBI with chronic cardiovascular diseases including hypertension, hyperlipidemia, and some obesity in civil- ian, military, and professional football populations (Boos et al., 2019; Eric Nyam et al., 2019; Grashow et al., 2023; Harrison et al., 2022; Memmini et al., 2021; Stewart et al., 2022). Some of these studies have limitations including use of patient self-report, small cohorts, or inclusion of patients with preexisting cardiovascular disease, Izzy noted. A retrospective cohort study using Department of Veterans Affairs (VA) data compared morbidities in 300,000 veterans with a history of TBI and 258,000 veterans without TBI (Stewart et al., 2022). The study identified a phenotype of composite cardiovascular comorbidity that was present in 28 percent of veterans with penetrating TBI. The next highest association with this phenotype was seen in moderate to severe TBI, followed by mild TBI. All forms of TBI had higher incidence of cardiovascular comorbidity than veterans without TBI. Izzy and colleagues conducted a 10-year study of TBI patients with no preexisting cardiovascular, psychiatric, endocrine, or neurological comor- bidities (Izzy et al., 2022). They found that both mild TBI and moderate to severe TBI were associated with increased cardiovascular risk as defined by coronary artery disease, hyperlipidemia, hypertension, and obesity. More- over, risk of these comorbidities after TBI was increased across age groups, including a significant increase in hypertension risk even in young individu- als with mild and moderate to severe TBI aged 18–40 years, he said. In subsequent research, Izzy found that a composite measure of cardiovascular disease aligned with patterns seen in isolated cardiovascular conditions, showing that individuals with mild or moderate to severe TBI were more likely to develop the disease compared to the uninjured control group (Izzy et al., 2023). After dipping in middle age, incidence of cardiovascular comorbidities such as hypertension rose in individuals aged 60 years and older, he reported. These findings demonstrate an association between TBI and chronic cardiovascular disease, he said. Numerous factors affect cognitive impairment and cardiovascular dys- function after TBI, Izzy continued, noting that cardiovascular disease may also play a role in chronic neurodegenerative disease, such as dementia (Izzy et al., 2023). Both preinjury factors, such as existing mental health conditions, lifestyle behaviors, and social determinants of health, and injury-specific characteristics such as severity and repetition can signifi- cantly influence long-term TBI outcomes (see Figure 2-3). Izzy highlighted the complex interplay between TBI and endocrine, psychiatric, neurologi- cal, and/or cardiovascular disorders, emphasizing the need for proactive screening to better define these associations and identify comorbidity- specific risk factors. PREPUBLICATION COPY—Uncorrected Proofs 

38 EXAMINING TBI AS A CHRONIC CONDITION FIGURE 2-3 Potential relationships connecting preinjury factors and brain injury to cognitive and cardiovascular dysfunction, including neurobiological changes, comorbidities, and behavioral or lifestyle factors that may collectively contribute to increased risk. SOURCE: Presented by Saef Izzy, March 11, 2025. From Izzy et al., 2023. Post-TBI Dementia Raquel C. Gardner, associate professor of neurology at Tel Aviv Uni- versity School of Medicine and Sheba Medical Center, Israel, outlined the increased risk for dementia among individuals with TBI, along with modi- fiable risk factors, associated pathology, and areas for further research. TBI is a well-established risk factor for dementia, she said. She highlighted findings from a recent meta-analysis that combined 41 risk estimates from studies involving 7.7 million individuals (Gardner et al., 2023a). The analy- sis found a 71 percent increased risk for all-cause dementia associated with TBI. In certain subpopulations, such as veterans with moderate to severe TBI, the increased risk of dementia was as high as 377 percent (Barnes et al., 2018). Gardner noted that differences in dementia risk can stem from the cumulative lifetime exposure to TBI, with greater frequency or severity elevating that risk. She noted that that the Lancet Commission on Dementia Prevention, Intervention, and Care formally recognized TBI as a modifiable risk factor in 2020, underscoring the strength of the evidence behind this association (Livingston et al., 2020). PREPUBLICATION COPY—Uncorrected Proofs 

TBI AS A CHRONIC CONDITION 39 Dementia Risk Factors Research programs on post-TBI dementia, including through the Department of Defense Congressionally Directed Medical Research Pro- gram, and the Long-Term Impact of Military-Relevant Brain Injury Con- sortium-Chronic Effects of Neurotrauma Consortium (LIMBIC-CENC), have generated valuable data, Gardner continued. A nationwide cohort study based on data from nearly 300,000 veterans in the Veterans Health Administration system explored whether reducing modifiable dementia risk factors, such as hypertension, diabetes, depression, and PTSD, could help prevent post-TBI dementia (Gardner et al., 2023b). The study found that while the risk of dementia associated with these factors was actually lower in veterans with prior TBI compared to those without, the prevalence of these conditions was significantly higher among TBI-exposed individu- als. For instance, hypertension was 1.2 times more common, depression 2.5 times, PTSD 3 times, and epilepsy 7 times more prevalent in veterans with TBI compared to veterans without TBI. Although modifying these conditions may yield less dementia risk reduction in individuals with TBI, Gardner concluded that their high prevalence suggests that addressing them could still have a substantial impact on reducing the overall burden of post-TBI dementia. Pathology of Post-TBI Dementia Researchers have explored whether the pathology of post-TBI dementia is the same or different than that of Alzheimer’s Disease (AD), said Gard- ner. A large study of autopsy cohorts and lifetime TBI exposure character- ized before death found a consistent association of TBI with Lewy body pathology, alpha-synuclein (i.e., the pathology of Parkinson’s disease and Lewy body dementia), and microvascular ischemia (Crane et al., 2016). Gardner noted that although this 2016 study found no association with amyloid beta—one of the pathognomonic features of AD—a subsequent cohort study found a higher burden of amyloid beta in individuals with TBI (Agrawal et al., 2022). Post-TBI dementia may not reflect a single disease pathology, she said, but rather may result from various pathologies that can occur in isolation or in combination in an individual. Next Steps The specific pathology of post-TBI dementia that develops in an indi- vidual will likely depend on the lifetime dose of TBI, personal genetics, and other lifetime exposures that increase or reduce risk, Gardner said. Epidemiological studies inform an understanding of the pathophysiology of PREPUBLICATION COPY—Uncorrected Proofs 

40 EXAMINING TBI AS A CHRONIC CONDITION post-TBI dementia, but much remains unknown, she said. With the advent of antiamyloid therapies like lecanemab, Gardner argued for a targeted shift toward screening, diagnosing, and treating post-TBI dementia, not- ing that it remains unclear whether existing AD research fully applies to post-TBI cases and whether emerging blood biomarker tests used to detect brain amyloid in AD are equally effective for diagnosing post-TBI demen- tia. Addressing these questions are critical steps in scaling up cost-effective screening and treatment, she said. Discussion TBI and Comorbidity Diagnosis Challenges During a discussion moderated by Hoffman, Bombardier highlighted that individuals with TBI are less likely to be diagnosed and treated for depression postinjury than they were preinjury. He speculated this may stem from clinicians attributing depressive symptoms to TBI itself rather than identifying a treatable comorbid condition. This diagnostic over- shadowing may lead to undertreatment of mental health issues in TBI populations, he said. Pugh emphasized similar diagnostic challenges in post- traumatic epilepsy care, where treatment resistance is significantly higher than in epilepsy alone. She endorsed the need for early TBI screening in patients with epilepsy to better anticipate potential resistance and enable proactive education for families. Overlooked Cognitive and Hormonal Effects Wexler described how cognitive deficits in TBI patients, particularly those with growth hormone deficiency (GHD), often go unrecognized because of normative cognitive test results that fail to reflect changes from individual patient baselines. These individuals may struggle with executive tasks, such as time management and self-expression, and are often forced to advocate for their needs despite these impairments, she said. Izzy added that cardiovascular problems in TBI patients are often overlooked or attributed solely to brain injury, leading to undertreatment. He advocated for broader screening of cardiovascular comorbidities in TBI patients and suggested that precision medicine approaches could help identify those at elevated risk. Such approaches can improve TBI care, Izzy suggested, by identifying subgroups of patients at higher risk for particular symptoms and outcomes based on information on the person and their injury, imaging findings, and other biological and clinical markers. For clinicians and patients, this type of approach could enable more tailored screening and interventions and more proactive management of long-term health effects, he said. PREPUBLICATION COPY—Uncorrected Proofs 

TBI AS A CHRONIC CONDITION 41 Antiamyloid Therapies and Post-TBI Risk Gardner noted that safety data on administering new antiamyloid drugs like lecanemab to patients with recent TBI remains lacking. Many treatment centers exclude these individuals from dementia treatment because of the unknown risks, including amyloid-related imaging abnormalities. She cited recent findings that one in 18 Medicare beneficiaries visited the emergency department for TBI over 18 years (Kornblith et al., 2024), underscoring the need for urgent research into the implications of TBI on dementia treatment. Age of Injury and Comorbidity Risk In response to questions about the influence of age at time of injury on comorbidities, Pugh explained that both PTE and epilepsy are more preva- lent among the very young and the elderly. Her research on veterans found that individuals reporting moderate or severe TBIs at younger ages had increased risk of epilepsy even if their injury was not service related. Wexler added that children, compared to adults, may more frequently recover from injury. Gardner’s meta-analysis showed a higher risk of dementia associated with younger age at injury (Gardner et al., 2023a), and a separate Califor- nia study found that mild TBI at age 80 carried similar dementia morbidity as severe TBI at age 50 (Gardner et al., 2014). Izzy again mentioned the increased incidence of cardiovascular comor- bidity rates, including hypertension, in individuals aged 18–40, regardless of TBI severity or previous heart conditions (Izzy et al., 2023). He noted his current research under review shows that some individuals as young as 40 develop dementia post-TBI. Bombardier added that while age does not appear to influence depression rates post-TBI, there are notable gen- erational and sex-based differences, with higher prevalence among women and younger generations. Improving Multimorbidity Data Collection and Monitoring Given the prevalence of multimorbidity and TBI, Hoffman asked about approaches to improve data collection and monitoring for these conditions. Wexler emphasized the need for better data collection tools and guidelines for conditions like PTHP, which can be time consuming to diagnose. She highlighted the importance of multidisciplinary care teams and consistent screening for persistent, function-limiting symptoms. Pugh noted findings from epilepsy research in post-9/11 veterans, which found that people with preexisting mental health issues often fare worse after a diagnosis of epilepsy. She recommended that ideal epilepsy care teams include mental PREPUBLICATION COPY—Uncorrected Proofs 

42 EXAMINING TBI AS A CHRONIC CONDITION health providers, neurologists, and primary care clinicians to manage com- plex comorbidities. Izzy said that precision medicine approaches that can better track comorbidity trajectories, such as how hypertension may relate to sub- sequent neuroendocrine or neurological conditions, will aid in monitor- ing patients and improving long-term outcomes. His team is investigating whether initial brain imaging can be used in identifying the specific location of the brain associated with the cardiovascular issue. For example, he said, researchers have found that the insular cortex, a part of the brain’s cerebral cortex that is located beneath a groove called the Sylvian fissure, is linked to the regulation of heart rate and other autonomic body responses, highlight- ing its role in brain–heart connections. Biomarkers and TBI Diagnosis Gardner emphasized the usefulness of implementing blood biomarker tests approved by the Food and Drug Administration (e.g., glial fibrillary acidic protein and ubiquitin C-terminal hydrolase) to diagnose mild TBI, especially when computed tomography imaging is negative. Many patients discharged from the emergency department without a TBI diagnosis expe- rience chronic symptoms that are hard to attribute definitively to TBI or psychological trauma, she said. TBI and acute psychological stress can also co-occur, such as in military populations that experience blast injuries, and may present similar symptoms years later. These factors complicate the pro- cess of diagnosing the cause of subsequent symptoms. Widespread use of bio- marker testing soon after injury would improve diagnostic accuracy, she said. Limitations in Depression Treatment Bombardier noted that that no biomarkers of depression have yet been identified and current treatments for depression in TBI populations— including antidepressants and cognitive behavioral therapy—have shown limited success. He proposed reframing depression as a secondary condi- tion, with treatment strategies tailored to comorbid symptoms like sleep disorders, chronic pain, or PTSD. Incorporating patient-reported outcomes and shared decision making can enhance engagement and effectiveness. This person-centered approach allows clinicians to prioritize interventions based on patient motivation and lifestyle, he said. Hormonal Deficiencies and Inflammation Addressing a question about hormone levels and neuroinflammatory signaling, Wexler noted that mouse studies have shown that both growth PREPUBLICATION COPY—Uncorrected Proofs 

TBI AS A CHRONIC CONDITION 43 hormone and testosterone are important for myelin repair. There is a need for further research on the interplay between neuroendocrine pathways and recovery from TBI, she said. Heat Sensitivity and TBI An audience member asked whether a known link exists between TBI and fainting in hot weather or crowded environments. Izzy responded that individuals with TBI may experience impaired temperature regulation due to hypothalamic damage, making them more vulnerable to heat-related issues like heat exhaustion or heat stroke. He is not aware of specific direct studies on this topic, but that a dehydration-induced feeling of lightheaded- ness (presyncope) is a plausible mechanism, especially in warmer climates. He added that more research is needed to determine whether inflammation or other physiological changes that predispose an individual with TBI to fainting is an area in need of future research. The Broad Effects of TBI and the Need for Longer-Term Surveillance Hoffman reiterated the diagnostic and treatment complexities of TBI, noting the challenge posed by overlapping and evolving symptoms. Bom- bardier expressed concern that conditions such as depression are often misattributed to TBI itself, resulting in underdiagnosis and missed oppor- tunities for early intervention in comorbidities like depression and epilepsy. Izzy and Gardner highlighted the need for longer-term research to better capture chronic outcomes such as cardiovascular disease, dementia, and multimorbidity that may emerge 3 to 5 years or more postinjury but are often missed because of short follow-up periods. While the TRACK-TBI longitudinal study represents progress, further investment is needed, Gard- ner said. Izzy concurred, noting that extended study timelines and funding will be essential for improving long-term understanding and care. Suggestions for Improved Care With TBI affecting millions across the life span, a shift toward preci- sion medicine, extended monitoring, and individualized care is essential to address the broad and complex effect of this condition, the panelists high- lighted. Wexler noted that cognitive limitations in TBI patients can hinder their ability to self-advocate or even recognize the need for care. Wexler and Pugh called for integrated care models that combine the expertise of neurologists, endocrinologists, physiatrists, primary care providers, and mental health professionals to deliver comprehensive, coordinated treat- ment. Gardner and Izzy underscored the value of precision tools such as PREPUBLICATION COPY—Uncorrected Proofs 

44 EXAMINING TBI AS A CHRONIC CONDITION blood biomarkers and genetic screening to identify individuals with TBI at higher risk for poor outcomes. Broader adoption of validated diagnostic tools, akin to those now standard in Alzheimer’s care, offers one of the most actionable steps to improving long-term outcomes, Gardner said. REFERENCES Agha, A., J. Phillips, P. O’Kelly, W. Tormey, and C. J. Thompson. 2005. The natural history of post-traumatic hypopituitarism: Implications for assessment and treatment. American Journal of Medicine 118(12):1416. Agrawal, S., S. E. Leurgans, B. D. James, L. L. Barnes, R. I. Mehta, K. Dams-O’Connor, J. Mez, D. A. Bennett, and J. A. Schneider. 2022. Association of traumatic brain injury with and without loss of consciousness with neuropathologic outcomes in community- dwelling older persons. JAMA Network Open 5(4):e229311. Aimaretti, G., M. R. Ambrosio, C. Di Somma, M. Gasperi, S. Cannavò, C. Scaroni, A. Fusco, P. Del Monte, E. De Menis, M. Faustini-Fustini, F. Grimaldi, F. Logoluso, P. Razzore, S. Rovere, S. Benvenga, E. C. Degli Uberti, L. De Marinis, G. Lombardi, F. Mantero, E. Martino, G. Giordano, and E. Ghigo. 2005. Residual pituitary function after brain injury-induced hypopituitarism: A prospective 12-month study. Journal of Clinical En- docrinology & Metabolism 90(11):6085-6092. Alavi, S. A., C. L. Tan, D. K. Menon, H. L. Simpson, and P. J. Hutchinson. 2016. Incidence of pituitary dysfunction following traumatic brain injury: A prospective study from a regional neurosurgical centre. British Journal of Neurosurgery 30(3):302-306. Alway, Y., K. R. Gould, L. Johnston, D. McKenzie, and J. Ponsford. 2016. A prospective ex- amination of axis I psychiatric disorders in the first 5 years following moderate to severe traumatic brain injury. Psychological Medicine 46(6):1331-1341. Andelic, N., E. I. Howe, T. Hellstrøm, M. F. Sanchez, J. Lu, M. Løvstad, and C. Røe. 2018. Disability and quality of life 20 years after traumatic brain injury. Brain and Behavior 8(7):e01018. Annegers, J. F., W. A. Hauser, S. P. Coan, and W. A. Rocca. 1998. A population-based study of seizures after traumatic brain injuries. New England Journal of Medicine 338(1):20-24. Barnes, D. E., A. L. Byers, R. C. Gardner, K. H. Seal, W. J. Boscardin, and K. Yaffe. 2018. Association of mild traumatic brain injury with and without loss of consciousness with dementia in US military veterans. JAMA Neurology 75(9):1055-1061. Baxter, D., D. J. Sharp, C. Feeney, D. Papadopoulou, T. E. Ham, S. Jilka, P. J. Hellyer, M. C. Patel, A. N. Bennett, A. Mistlin, E. McGilloway, M. Midwinter, and A. P. Goldstone. 2013. Pituitary dysfunction after blast traumatic brain injury: The UK BIOSAP study. Annals of Neurology 74(4):527-536. Bhagia, V., C. Gilkison, R. H. Fitts, D. J. Zgaljardic, W. M. High, Jr., B. E. Masel, R. J. Ur- ban, and K. A. Mossberg. 2010. Effect of recombinant growth hormone replacement in a growth hormone deficient subject recovering from mild traumatic brain injury: A case report. Brain Injury 24(3):560-567. Bombardier, C. H., K. R. Bell, N. R. Temkin, J. R. Fann, J. Hoffman, and S. Dikmen. 2009. The efficacy of a scheduled telephone intervention for ameliorating depressive symptoms during the first year after traumatic brain injury. Journal of Head Trauma Rehabilitation 24(4):230-238. Bombardier, C. H., J. R. Fann, N. R. Temkin, P. C. Esselman, J. Barber, and S. S. Dikmen. 2010. Rates of major depressive disorder and clinical outcomes following traumatic brain injury. JAMA 303(19):1938-1945. PREPUBLICATION COPY—Uncorrected Proofs 

TBI AS A CHRONIC CONDITION 45 Bondanelli, M., L. De Marinis, M. R. Ambrosio, M. Monesi, D. Valle, M. C. Zatelli, A. Fusco, A. Bianchi, M. Farneti, and E. C. degli Uberti. 2004. Occurrence of pituitary dysfunction following traumatic brain injury. Journal of Neurotrauma 21(6):685-696. Boos, C. J., N. De Villiers, D. Dyball, A. McConnell, and A. N. Bennett. 2019. The relation- ship between military combat and cardiovascular risk: A systematic review and meta- analysis. International Journal of Vascular Medicine 2019:9849465. Casano-Sancho, P., L. Suárez, L. Ibáñez, G. García-Fructuoso, J. Medina, and A. Febrer. 2013. Pituitary dysfunction after traumatic brain injury in children: Is there a need for ongoing endocrine assessment? Clinical Endocrinology 79(6):853-858. Ciarlone, S. L., J. K. Statz, J. A. Goodrich, J. N. Norris, C. W. Goforth, S. T. Ahlers, and A. E. Tschiffely. 2020. Neuroendocrine function and associated mental health outcomes following mild traumatic brain injury in OEF-deployed service members. Journal of Neuroscience Research 98(6):1174-1187. Cole, J. H., R. Leech, and D. J. Sharp. 2015. Prediction of brain age suggests accelerated atrophy after traumatic brain injury. Annals of Neurology 77(4):571-581. Coppalini, G., M. Salvagno, L. Peluso, E. G. Bogossian, A. Quispe Cornejo, V. Labbé, F. Annoni, and F. S. Taccone. 2024. Cardiac injury after traumatic brain injury: Clinical consequences and management. Neurocritical Care 40(2):477-485. Corrigan, J. D., J. P. Cuthbert, C. Harrison-Felix, G. G. Whiteneck, J. M. Bell, A. C. Miller, V. G. Coronado, and C. R. Pretz. 2014. US population estimates of health and social outcomes 5 years after rehabilitation for traumatic brain injury. Journal of Head Trauma Rehabilitation 29(6):E1-E9. Crane, P. K., L. E. Gibbons, K. Dams-O’Connor, E. Trittschuh, J. B. Leverenz, C. D. Keene, J. Sonnen, T. J. Montine, D. A. Bennett, S. Leurgans, J. A. Schneider, and E. B. Larson. 2016. Association of traumatic brain injury with late-life neurodegenerative conditions and neuropathologic findings. JAMA Neurology 73(9):1062-1069. Cuesta, M., M. J. Hannon, R. K. Crowley, L. A. Behan, W. Tormey, D. Rawluk, M. Delargy, A. Agha, and C. J. Thompson. 2016. Symptoms of gonadal dysfunction are more predic- tive of hypopituitarism than nonspecific symptoms in screening for pituitary dysfunction following moderate or severe traumatic brain injury. Clinical Endocrinology 84(1):92-98. Dams-O’Connor, K., K. T. L. Sy, A. Landau, Y. Bodien, S. Dikmen, E. R. Felix, J. T. Giacino, L. Gibbons, F. M. Hammond, T. Hart, D. Johnson-Greene, J. Lengenfelder, A. Lequerica, J. Newman, T. Novack, T. M. O’Neil-Pirozzi, and G. Whiteneck. 2018. The feasibility of telephone-administered cognitive testing in individuals 1 and 2 years after inpatient rehabilitation for traumatic brain injury. Journal of Neurotrauma 35(10):1138-1145. Dams-O’Connor, K., A. C. Seifert, J. F. Crary, B. N. Delman, M. R. Del Bigio, G. G. Kovacs, E. B. Lee, A. L. Nolan, A. Pruyser, E. Selmanovic, W. Stewart, E. Woodoff-Leith, and R. D. Folkerth. 2023a. The neuropathology of intimate partner violence. Acta Neuro- pathologica 146(6):803-815. Dams-O’Connor, K., S. B. Juengst, J. Bogner, N. D. Chiaravalloti, J. D. Corrigan, J. T. Giacino, C. L. Harrison-Felix, J. M. Hoffman, J. M. Ketchum, A. H. Lequerica, J. H. Marwitz, A. C. Miller, R. Nakase-Richardson, A. R. Rabinowitz, A. M. Sander, R. Zafonte, and F. M. Hammond. 2023b. Traumatic brain injury as a chronic disease: Insights from the United States Traumatic Brain Injury Model Systems Research Program. Lancet Neurol- ogy 22(6):517-528. Del Pozzo, J., L. Spielman, B. Yew, D. M. Shpigel, E. Selamanovic, and K. Dams-O’Connor. 2024. Detecting and predicting cognitive decline in individuals with traumatic brain injury: A longitudinal telephone-based study. Journal of Neurotrauma 41(15-16):1937-1947. PREPUBLICATION COPY—Uncorrected Proofs 

46 EXAMINING TBI AS A CHRONIC CONDITION Doran, S. J., R. J. Henry, K. A. Shirey, J. P. Barrett, R. M. Ritzel, W. Lai, J. C. Blanco, A. I. Faden, S. N. Vogel, and D. J. Loane. 2020. Early or late bacterial lung infection increases mortality after traumatic brain injury in male mice and chronically impairs monocyte innate immune function. Critical Care Medicine 48(5):e418-e428. Elser, H., R. F. Gottesman, A. E. Walter, J. Coresh, R. Diaz-Arrastia, T. H. Mosley, and A. L. C. Schneider. 2023. Head injury and long-term mortality risk in community-dwelling adults. JAMA Neurology 80(3):260-269. Elser, H., L. W. Pappalardo, R. F. Gottesman, J. Coresh, R. Diaz-Arrastia, T. H. Mosley, S. E. Kasner, S. Koton, and A. L. C. Schneider. 2024. Head injury and risk of incident ischemic stroke in community-dwelling adults. Stroke 55(6):1562-1571. Emrani, S., A. Koutures, Y. Tripodis, M. Uretsky, B. Abdolmohammadi, C. Nowinski, D. H. Daneshvar, B. Dwyer, D. I. Katz, L. E. Goldstein, R. C. Cantu, B. M. Martin, J. N. Palmisano, K. Dams-O’Connor, J. F. Crary, R. A. Stern, J. Mez, V. E. Alvarez, B. R. Huber, A. C. McKee, T. D. Stein, and M. L. Alosco. 2025. Characterizing white mat- ter and vascular pathologies in brain donors exposed to repetitive head impacts. Acta Neuropathologica 149(1):24. Eric Nyam, T.-T., C.-H. Ho, C.-C. Chio, S.-W. Lim, J.-J. Wang, C.-H. Chang, J.-R. Kuo, and C.-C. Wang. 2019. Traumatic brain injury increases the risk of major adverse cardiovascular and cerebrovascular events: A 13-year, population-based study. World Neurosurgery 122:e740-e753. Fann, J. R., W. J. Katon, J. M. Uomoto, and P. C. Esselman. 1995. Psychiatric disorders and functional disability in outpatients with traumatic brain injuries. American Journal of Psychiatry 152(10):1493-1499. Gardner, R. C., J. F. Burke, J. Nettiksimmons, A. Kaup, D. E. Barnes, and K. Yaffe. 2014. Dementia risk after traumatic brain injury vs nonbrain trauma: The role of age and sever- ity. JAMA Neurology 71(12):1490-1497. Gardner, R. C., A. Bahorik, E. S. Kornblith, I. E. Allen, B. L. Plassman, and K. Yaffe. 2023a. Systematic review, meta-analysis, and population attributable risk of dementia associ- ated with traumatic brain injury in civilians and veterans. Journal of Neurotrauma 40(7-8):620-634. Gardner, R. C., D. E. Barnes, Y. Li, J. Boscardin, C. Peltz, and K. Yaffe. 2023b. Medical and psychiatric risk factors for dementia in veterans with and without traumatic brain injury (TBI): A nationwide cohort study. Journal of Prevention of Alzheimer’s Disease 10(2):244-250. Gomez-Hernandez, R., J. E. Max, T. Kosier, S. Paradiso, and R. G. Robinson. 1997. Social impairment and depression after traumatic brain injury. Archives of Physical Medicine and Rehabilitation 78(12):1321-1326. Grashow, R., C. O. Tan, S. Izzy, H. A. Taylor, Jr., M. G. Weisskopf, M. M. Wasfy, A. J. Whit- tington, F. Speizer, R. Zafonte, and A. L. Baggish. 2023. Association between concussion burden during professional American-style football and postcareer hypertension. Circula- tion 147(14):1112-1114. Gregory, T., and M. Smith. 2012. Cardiovascular complications of brain injury. Continuing Education in Anaesthesia Critical Care & Pain 12(2):67-71. Hammond, F. M., J. T. Giacino, R. Nakase Richardson, M. Sherer, R. D. Zafonte, J. Whyte, D. B. Arciniegas, and X. Tang. 2019. Disorders of consciousness due to traumatic brain injury: Functional status ten years post-injury. Journal of Neurotrauma 36(7):1136-1146. Hanscom, M., D. J. Loane, and T. Shea-Donohue. 2021. Brain-gut axis dysfunction in the pathogenesis of traumatic brain injury. Journal of Clinical Investigation 131(12): e143777. PREPUBLICATION COPY—Uncorrected Proofs 

TBI AS A CHRONIC CONDITION 47 Harrison, A., A. Lane-Cordova, M. F. La Fountaine, and R. D. Moore. 2022. Concussion history and heart rate variability during bouts of acute stress. Journal of Athletic Train- ing 57(8):741-747. Henry, R. J., R. M. Ritzel, J. P. Barrett, S. J. Doran, Y. Jiao, J. B. Leach, G. L. Szeto, J. Wu, B. A. Stoica, A. I. Faden, and D. J. Loane. 2020. Microglial depletion with CSF1R inhibitor during chronic phase of experimental traumatic brain injury reduces neurodegeneration and neurological deficits. Journal of Neuroscience 40(14):2960-2974. High, W. M., Jr., M. Briones-Galang, J. A. Clark, C. Gilkison, K. A. Mossberg, D. J. Zgal- jardic, B. E. Masel, and R. J. Urban. 2010. Effect of growth hormone replacement ther- apy on cognition after traumatic brain injury. Journal of Neurotrauma 27(9):1565-1575. Hoffman, J. M., M. Curran, J. Barber, S. Lucas, J. R. Fann, and J. M. Zumsteg. 2024. Col- laborative care for chronic pain after traumatic brain injury: A randomized clinical trial. JAMA Network Open 7(6):e2413459. Hoge, C. W., D. McGurk, J. L. Thomas, A. L. Cox, C. C. Engel, and C. A. Castro. 2008. Mild traumatic brain injury in U.S. soldiers returning from Iraq. New England Journal of Medicine 358(5):453-463. Holsinger, T., D. C. Steffens, C. Phillips, M. J. Helms, R. J. Havlik, J. C. Breitner, J. M. Gu- ralnik, and B. L. Plassman. 2002. Head injury in early adulthood and the lifetime risk of depression. Archives of General Psychiatry 59(1):17-22. Howlett, J. R., L. D. Nelson, and M. B. Stein. 2022. Mental health consequences of traumatic brain injury. Biological Psychiatry 91(5):413-420. Hunzinger, K. J., C. A. Law, H. Elser, A. E. Walter, B. G. Windham, P. Palta, S. P. Juraschek, C. W. Hicks, R. F. Gottesman, and A. L. C. Schneider. 2023. Associations between head injury and subsequent risk of falls: Results from the Atherosclerosis Risk in Communities (ARIC) Study. Neurology 101(22):e2234-e2242. Hunzinger, K. J., A. E. Walter, K. A. Rosenthal, B. G. Windham, P. Palta, S. P. Juraschek, C. W. Hicks, R. F. Gottesman, and A. L. C. Schneider. 2024. Associations between prior head injury, physical functioning, and frailty in the Atherosclerosis Risk in Communities Study. Journals of Gerontology Series A: Biological Sciences and Medical Sciences 79(4). Izzo, G., A. Tirelli, E. Angrisani, G. Cannaviello, L. Cannaviello, A. Puzziello, A. Vatrella, and M. Vitale. 2016. Pituitary dysfunction and its association with quality of life in traumatic brain injury. International Journal of Surgery 28(Suppl 1):S103-S108. Izzy, S., P. M. Chen, Z. Tahir, R. Grashow, F. Radmanesh, D. J. Cote, T. Yahya, A. Dhand, H. Taylor, S. L. Shih, O. Albastaki, C. Rovito, S. B. Snider, M. Whalen, D. M. Nathan, K. K. Miller, F. E. Speizer, A. Baggish, M. G. Weisskopf, and R. Zafonte. 2022. Association of traumatic brain injury with the risk of developing chronic cardiovascular, endocrine, neurological, and psychiatric disorders. JAMA Network Open 5(4):e229478. Izzy, S., R. Grashow, F. Radmanesh, P. Chen, H. Taylor, R. Formisano, F. Wilson, M. Wasfy, A. Baggish, and R. Zafonte. 2023. Long-term risk of cardiovascular disease after traumatic brain injury: Screening and prevention. Lancet Neurology 22(10):959-970. Johnson, V. E., J. E. Stewart, F. D. Begbie, J. Q. Trojanowski, D. H. Smith, and W. Stewart. 2013. Inflammation and white matter degeneration persist for years after a single trau- matic brain injury. Brain 136(Pt 1):28-42. Kaulfers, A. M., P. F. Backeljauw, K. Reifschneider, S. Blum, L. Michaud, M. Weiss, and S. R. Rose. 2010. Endocrine dysfunction following traumatic brain injury in children. Journal of Pediatrics 157(6):894-899. Kelly, D. F., C. Chaloner, D. Evans, A. Mathews, P. Cohan, C. Wang, R. Swerdloff, M. S. Sim, J. Lee, M. J. Wright, C. Kernan, G. Barkhoudarian, K. C. Yuen, and K. Guskiewicz. 2014. Prevalence of pituitary hormone dysfunction, metabolic syndrome, and impaired quality of life in retired professional football players: A prospective study. Journal of Neurotrauma 31(13):1161-1171. PREPUBLICATION COPY—Uncorrected Proofs 

48 EXAMINING TBI AS A CHRONIC CONDITION Kishi, Y., R. G. Robinson, and J. T. Kosier. 2001. Suicidal ideation among patients with acute life-threatening physical illness: Patients with stroke, traumatic brain injury, myocardial infarction, and spinal cord injury. Psychosomatics 42(5):382-390. Kornblith, E., L. G. Diaz-Ramirez, K. Yaffe, W. J. Boscardin, and R. C. Gardner. 2024. Inci- dence of traumatic brain injury in a longitudinal cohort of older adults. JAMA Network Open 7(5):e2414223. Krahulik, D., D. Aleksijevic, V. Smolka, E. Klaskova, P. Venhacova, M. Vaverka, V. Mihal, and J. Zapletalova. 2017. Prospective study of hypothalamo-hypophyseal dysfunction in children and adolescents following traumatic brain injury. Biomedical Papers of the Medical Faculty of the University Palacky, Olomouc, Czech Republic 161(1):80-85. Kreber, L. A., G. S. Griesbach, and M. J. Ashley. 2016. Detection of growth hormone deficiency in adults with chronic traumatic brain injury. Journal of Neurotrauma 33(17):1607-1613. Krishnamoorthy, V., A. Rowhani-Rahbar, E. F. Gibbons, F. P. Rivara, N. R. Temkin, N. Chai- kittisilpa, K. Luk, and M. S. Vavilala. 2017. The authors reply. Critical Care Medicine 45(11):e1194-e1195. Kumar, R. G., S. Gao, S. B. Juengst, A. K. Wagner, and A. Fabio. 2018. The effects of post- traumatic depression on cognition, pain, fatigue, and headache after moderate-to-severe traumatic brain injury: A thematic review. Brain Injury 32(4):383-394. Kumar, R. G., J. M. Ketchum, J. D. Corrigan, F. M. Hammond, M. Sevigny, and K. Dams- O’Connor. 2020. The longitudinal effects of comorbid health burden on functional outcomes for adults with moderate to severe traumatic brain injury. Journal of Head Trauma Rehabilitation 35(4):E372-E381. Lee J., L. J. Anderson, D. Migula, K. C. J. Yuen, L. McPeak, and J. M. Garcia. 2021. Experi- ence of a pituitary clinic for US military veterans with traumatic brain injury. Journal of the Endocrine Society 5(4):bvab005. Livingston, G., J. Huntley, A. Sommerlad, D. Ames, C. Ballard, S. Banerjee, C. Brayne, A. Burns, J. Cohen-Mansfield, C. Cooper, S. G. Costafreda, A. Dias, N. Fox, L. N. Gitlin, R. Howard, H. C. Kales, M. Kivimäki, E. B. Larson, A. Ogunniyi, V. Orgeta, K. Ritchie, K. Rockwood, E. L. Sampson, Q. Samus, L. S. Schneider, G. Selbæk, L. Teri, and N. Mukadam. 2020. Dementia prevention, intervention, and care: 2020 report of the Lancet Commission. Lancet 396(10248):413-446. Loane, D. J., A. Kumar, B. A. Stoica, R. Cabatbat, and A. I. Faden. 2014. Progressive neu- rodegeneration after experimental brain trauma: Association with chronic microglial activation. Journal of Neuropathology and Experimental Neurology 73(1):14-29. Malec, J. F., J. M. Ketchum, F. M. Hammond, J. D. Corrigan, K. Dams-OʼConnor, T. Hart, T. Novack, M. Dahdah, G. G. Whiteneck, and J. Bogner. 2019. Longitudinal effects of medical comorbidities on functional outcome and life satisfaction after traumatic brain injury: An individual growth curve analysis of NIDILRR traumatic brain injury model system data. Journal of Head Trauma Rehabilitation 34(5):E24-E35. Manely, G. T., K. Dams-O’Connor, M. L. Alosco, H. O. Awwad, J. J. Bazarian, P. Bragge, J. D. Corrigan, A. Doperalski, A. R. Ferguson, C. L. Mac Donald, D. K. Menon, M. M. McNett, J. van der Naalt, L. D. Nelson, D. Pisică, N. D. Silverberg, N. Umoh, L. Wilson, E. L. Yuh, H. Zetterberg, A. I. R. Maas, M. A. McCrea, NIH-NINDS TBI Clas- sification and Nomenclature Initiative. 2025. A new characterisation of acute traumatic brain injury: The NIH-NINDS TBI Classification and Nomenclature Initiative. Lancet Neurology 24(6):512-523. Meisel, C., J. M. Schwab, K. Prass, A. Meisel, and U. Dirnagl. 2005. Central nervous system injury-induced immune deficiency syndrome. Nature Reviews Neuroscience 6(10):775-786. PREPUBLICATION COPY—Uncorrected Proofs 

TBI AS A CHRONIC CONDITION 49 Memmini, A. K., M. F. La Fountaine, S. P. Broglio, and R. D. Moore. 2021. Long-term influ- ence of concussion on cardio-autonomic function in adolescent hockey players. Journal of Athletic Training 56(2):141-147. Miller A. L., M. Bhattacharyya, R. Bhattacharyya, F. Frankhauser, L. E. Miller. 2023. Determi- nants of life dissatisfaction among adults in the United States: A cross-sectional analysis of the National Health Interview Survey. Medicine 102(32):e34488. Milleville, K. A., N. Awan, D. Disanto, R. G. Kumar, and A. K. Wagner. 2020. Early chronic systemic inflammation and associations with cognitive performance after moderate to severe TBI. Brain, Behavior, & Immunity - Health 11:100185. NASEM (National Academies of Sciences, Engineering, and Medicine). 2022. Traumatic brain injury: A roadmap for accelerating progress. Washington, DC: The National Academies Press. Niederland, T., H. Makovi, V. Gál, B. Andréka, C. S. Abrahám, and J. Kovács. 2007. Ab- normalities of pituitary function after traumatic brain injury in children. Journal of Neurotrauma 24(1):119-127. Personnier, C., H. Crosnier, P. Meyer, M. Chevignard, I. Flechtner, N. Boddaert, S. Breton, C. Mignot, Y. Dassa, J. C. Souberbielle, M. Piketty, K. Laborde, J. P. Jais, M. Viaud, S. Puget, C. Sainte-Rose, and M. Polak. 2014. Prevalence of pituitary dysfunction after severe traumatic brain injury in children and adolescents: A large prospective study. Journal of Clinical Endocrinology & Metabolism 99(6):2052-2060. Pretz, C. R., and K. Dams-O’Connor. 2013. Longitudinal description of the Glasgow Outcome Scale-Extended for individuals in the Traumatic Brain Injury Model Systems National Database: A National Institute on Disability and Rehabilitation Research traumatic brain injury model systems study. Archives of Physical Medicine and Rehabilitation 94(12):2486-2493. Pugh, M. J., E. Kennedy, J. J. Gugger, J. Mayo, D. Tate, A. Swan, J. Kean, H. Altalib, S. Gowda, A. Towne, S. Hinds, A. Van Cott, M. R. Lopez, C. A. Jaramillo, B. C. Eapen, R. R. McCafferty, M. Salinsky, J. Cramer, K. K. McMillan, A. Kalvesmaki, R. Diaz-Ar- rastia, and the MINUTE Study Group. 2021. The military injuries: Understanding post- traumatic epilepsy study: Understanding relationships among lifetime traumatic brain injury history, epilepsy, and quality of life. Journal of Neurotrauma 38(20):2841-2850. Pugh, M. J., H. Munger Clary, M. Myers, E. Kennedy, M. Amuan, A. A. Swan, S. Hinds, W. C. LaFrance, H. Altalib, A. Towne, A. Henion, A. White, C. Baca, and C.-P. Wang. 2025. Distinct comorbidity phenotypes among post-9/11 veterans with epilepsy are linked to diverging outcomes and mortality risks. Epilepsia 66(1):170-183. Ramlackhansingh, A. F., D. J. Brooks, R. J. Greenwood, S. K. Bose, F. E. Turkheimer, K. M. Kinnunen, S. Gentleman, R. A. Heckemann, K. Gunanayagam, G. Gelosa, and D. J. Sharp. 2011. Inflammation after trauma: Microglial activation and traumatic brain injury. Annals of Neurology 70(3):374-383. Rao, V., U. McCann, D. Han, A. Bergey, and M. T. Smith. 2014. Does acute TBI-related sleep disturbance predict subsequent neuropsychiatric disturbances? Brain Injury 28(1):20-26. Rapoport, M. J., S. McCullagh, P. Shammi, and A. Feinstein. 2005. Cognitive impairment associated with major depression following mild and moderate traumatic brain injury. Journal of Neuropsychiatry and Clinical Neurosciences 17(1):61-65. Regal, M., C. Páramo, S. M. Sierra, and R. V. Garcia-Mayor. 2001. Prevalence and incidence of hypopituitarism in an adult Caucasian population in northwestern Spain. Clinical Endocrinology 55(6):735-740. Ritzel, R. M., S. J. Doran, J. P. Barrett, R. J. Henry, E. L. Ma, A. I. Faden, and D. J. Loane. 2018. Chronic alterations in systemic immune function after traumatic brain injury. Journal of Neurotrauma 35(13):1419-1436. PREPUBLICATION COPY—Uncorrected Proofs 

50 EXAMINING TBI AS A CHRONIC CONDITION Sandsmark, D. K., A. Bashir, C. L. Wellington, and R. Diaz-Arrastia. 2019. Cerebral micro- vascular injury: A potentially treatable endophenotype of traumatic brain injury-induced neurodegeneration. Neuron 103(3):367-379. Sariaslan, A., D. J. Sharp, B. M. D’Onofrio, H. Larsson, and S. Fazel. 2016. Long-term out- comes associated with traumatic brain injury in childhood and adolescence: A nationwide Swedish cohort study of a wide range of medical and social outcomes. PLoS Medicine 13(8):e1002103. Satz, P., D. L. Forney, K. Zaucha, R. R. Asarnow, R. Light, C. McCleary, H. Levin, D. Kelly, M. Bergsneider, D. Hovda, N. Martin, N. Namerow, and D. Becker. 1998. Depression, cognition, and functional correlates of recovery outcome after traumatic brain injury. Brain Injury 12(7):537-553. Scheiblich, H., M. Trombly, A. Ramirez, and M. T. Heneka. 2020. Neuroimmune connections in aging and neurodegenerative diseases. Trends in Immunology 41(4):300-312. Schneider, A. L. C., D. Wang, G. Ling, R. F. Gottesman, and E. Selvin. 2018. Prevalence of self-reported head injury in the United States. New England Journal of Medicine 379(12):1176-1178. Schneider, A. L. C., E. Selvin, L. Latour, L. C. Turtzo, J. Coresh, T. Mosley, G. Ling, and R. F. Gottesman. 2021a. Head injury and 25-year risk of dementia. Alzheimers & Dementia 17(9):1432-1441. Schneider, A. L. C., D. Wang, R. F. Gottesman, and E. Selvin. 2021b. Prevalence of disability associated with head injury with loss of consciousness in adults in the United States: A population-based study. Neurology 97(2):e124-e135. Schneider, A. L. C., R. F. Gottesman, G. L. Krauss, J. Gugger, R. Diaz-Arrastia, A. Kucharska- Newton, J. Huang, and E. L. Johnson. 2022. Association of head injury with late- onset epilepsy: Results from the atherosclerosis risk in communities cohort. Neurology 98(8):e808-e817. Schneider, A. L. C., C. B. Peltz, Y. Li, A. Bahorik, R. C. Gardner, and K. Yaffe. 2023. Trau- matic brain injury and long-term risk of stroke among US military veterans. Stroke 54(8):2059-2068. Schneider, A. L. C., C. A. Law, R. F. Gottesman, G. Krauss, J. Huang, A. Kucharska-Newton, F. E. Jensen, J. J. Gugger, R. Diaz-Arrastia, and E. L. Johnson. 2024a. Posttraumatic epilepsy and dementia risk. JAMA Neurology 81(4):346-353. Schneider, A. L. C., J. R. Pike, H. Elser, J. Coresh, T. H. Mosley, R. Diaz-Arrastia, and R. F. Gottesman. 2024b. Traumatic brain injury and cognitive change over 30 years among community-dwelling older adults. Alzheimers & Dementia 20(9):6232-6242. Schneider, H. J., M. Schneider, B. Saller, S. Petersenn, M. Uhr, B. Husemann, F. von Rosen, and G. K. Stalla. 2006. Prevalence of anterior pituitary insufficiency 3 and 12 months after traumatic brain injury. European Journal of Endocrinology 154(2):259-265. Shaik, N. F., C. A. Law, H. Elser, and A. L. C. Schneider. 2024. Trends in traumatic brain injury mortality in the US. JAMA Neurology 81(2):194-195. Silva, P. P., S. Bhatnagar, S. D. Herman, R. Zafonte, A. Klibanski, K. K. Miller, and N. A. Tri- tos. 2015. Predictors of hypopituitarism in patients with traumatic brain injury. Journal of Neurotrauma 32(22):1789-1795. Smith, D. H., V. E. Johnson, and W. Stewart. 2013. Chronic neuropathologies of single and repetitive TBI: Substrates of dementia? Nature Reviews Neurology 9(4):211-221. Stewart, I. J., M. E. Amuan, C. P. Wang, E. Kennedy, K. Kenney, J. K. Werner, K. F. Carlson, D. F. Tate, T. K. Pogoda, C. E. Dismuke-Greer, W. S. Wright, E. A. Wilde, and M. J. Pugh. 2022. Association between traumatic brain injury and subsequent cardiovascular disease among post-9/11-era veterans. JAMA Neurology 79(11):1122-1129. Tanriverdi, F., and F. Kelestimur. 2015. Pituitary dysfunction following traumatic brain injury: Clinical perspectives. Neuropsychiatric Disease and Treatment 11:1835-1843. PREPUBLICATION COPY—Uncorrected Proofs 

TBI AS A CHRONIC CONDITION 51 Tanriverdi, F., K. Unluhizarci, Z. Karaca, F. F. Casanueva, and F. Kelestimur. 2010. Hypopitu- itarism due to sports related head trauma and the effects of growth hormone replacement in retired amateur boxers. Pituitary 13(2):111-114. Tanriverdi, F., A. De Bellis, H. Ulutabanca, A. Bizzarro, A. A. Sinisi, G. Bellastella, V. Amore- sano Paglionico, L. Dalla Mora, A. Selcuklu, K. Unluhizarci, F. F. Casanueva, and F. Kelestimur. 2013. A five year prospective investigation of anterior pituitary function after traumatic brain injury: Is hypopituitarism long-term after head trauma associated with autoimmunity? Journal of Neurotrauma 30(16):1426-1433. Teasdale, T. W., and A. W. Engberg. 2001. Suicide after traumatic brain injury: A population study. Journal of Neurology, Neurosurgery and Psychiatry 71(4):436-440. Uiterwijk, D., R. Stargatt, S. Humphrey, and S. F. Crowe. 2022. The relationship between cognitive functioning and symptoms of depression, anxiety, and post-traumatic stress disorder in adults with a traumatic brain injury: A meta-analysis. Neuropsychology Review 32(4):758-806. Undurti, A., E. A. Colasurdo, C. L. Sikkema, J. S. Schultz, E. R. Peskind, K. F. Pagulayan, and C. W. Wilkinson. 2018. Chronic hypopituitarism associated with increased postconcus- sive symptoms is prevalent after blast-induced mild traumatic brain injury. Frontiers in Neurology 9:72. Wagner, A. K. 2010. TBI translational rehabilitation research in the 21st century: Exploring a rehabilomics research model. European Journal of Physical and Rehabilitation Medicine 46(4):549-556. Wexler, T. L. 2023. Neuroendocrine disruptions following head injury. Current Neurology and Neuroscience Reports 23(5):213-224. WHO (World Health Organization). 2001. International Classification of Functioning, Dis- ability and Health (ICF). Geneva, Switzerland: World Health Organization. Whyte, J., R. Nakase-Richardson, F. M. Hammond, S. McNamee, J. T. Giacino, K. Kalmar, B. D. Greenwald, S. A. Yablon, and L. J. Horn. 2013. Functional outcomes in traumatic disorders of consciousness: 5-year outcomes from the National Institute on Disability and Rehabilitation Research traumatic brain injury model systems. Archives of Physical Medicine and Rehabilitation 94(10):1855-1860. Wickwire, E. M., J. S. Albrecht, V. F. Capaldi, 2nd, S. Jain, R. C. Gardner, M. T. Smith, S. G. Williams, J. Collen, D. M. Schnyer, J. T. Giacino, L. D. Nelson, P. Mukherjee, X. Sun, J. K. Werner, C. B. Mosti, A. J. Markowitz, G. T. Manley, and A. D. Krystal. 2023. As- sociation between insomnia and mental health and neurocognitive outcomes following traumatic brain injury. Journal of Neurotrauma. 40(21-22):2376-2385. Yang, A., S. Y. Cho, M. J. Kwak, S. J. Kim, S. W. Park, D. K. Jin, and J. E. Lee. 2019. Impact of BMI on peak growth hormone responses to provocative tests and therapeutic outcome in children with growth hormone deficiency. Scientific Reports 9(1):16181. Yu, T., X. Liu, L. Sun, J. Wu, and Q. Wang. 2021. Clinical characteristics of post-traumatic epilepsy and the factors affecting the latency of PTE. BMC Neurology 21(1):301. Yuen, K. C. J., B. Masel, M. S. Jaffee, G. O’Shanick, T. L. Wexler, K. Reifschneider, R. J. Ur- ban, S. Hoang, N. Kelepouris, and A. R. Hoffman. 2022. A consensus on optimization of care in patients with growth hormone deficiency and mild traumatic brain injury. Growth Hormone & IGF Research 66:101495. PREPUBLICATION COPY—Uncorrected Proofs 

PREPUBLICATION COPY—Uncorrected Proofs